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Biomedical subjects

A G Jones

Publications and source records attributed to A G Jones.

At least 55 records · Page 3Linked to original sources
PubMed1995

Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study.

The trends in treatment and outcome of 13,560 patients with pancreatic cancer, and in incidence of the disease, in the West Midlands health region were determined between 1957 and 1986 using data from the West Midlands Region Cancer Registry. Patients were divided into those diagnosed in the first 20 years (1957-1976, n = 7888) and the most recent 10 years (1977-1986, n = 5672). The disease was more common in men and the incidence increased up to 1970 after which it levelled off. In the 1977-1986 period a lower proportion of patients had laparotomy alone (825 (14.5 per cent) versus 1552 (19.7 per cent)), a similar proportion had bypass surgery (2010 (35.4 per cent) versus 2760 (35.0 per cent)), while a greater proportion had supportive care (2710 (47.8 per cent) versus 3368 (42.7 per cent)) but the resection rates were the same (145 (2.6 per cent) versus 208 (2.6 per cent)). The 30-day mortality rates between the two periods improved for resection (40 (27.6 per cent) versus 94 (45.2 per cent)), bypass surgery (436 (21.7 percent) versus 691 (25.0 per cent)) and laparotomy (372 (45.1 per cent) versus 873 (56.3 per cent)). The 12-month survival rate for bypass did not significantly differ during the study (14.9 per cent versus 12.4 per cent) but there was a significant improvement in the 5-year survival for resection (9.7 per cent versus 2.6 per cent, P < 0.015). The resection rates were low and 30-day mortality rates for surgery were high compared with those of other published series.

Actuarial Analysis↗
PubMed1994

Mitochondrial localization and characterization of 99Tc-SESTAMIBI in heart cells by electron probe X-ray microanalysis and 99Tc-NMR spectroscopy.

As the development of targeted intracellular magnetic resonance contrast agents proceeds, techniques for the quantitative analysis of the subcellular compartmentation and characterization of metallopharmaceuticals must also advance. To this end, the subcellular distribution and chemical state of hexakis (2-methoxyisobutyl isonitrile) technetium-99 (99Tc-SESTAMIBI), the ground state of the organotechnetium radiopharmaceutical used for the noninvasive evaluation of myocardial perfusion and viability by scintigraphy, has been determined by a novel application of electron probe X-ray microanalysis (EPXMA) and 99Tc-NMR spectroscopy. In cryopreserved cultured chick heart cells equilibrated in 36 microM 99Tc-SESTAMIBI, EPXMA imaging of mitochondria yielded a respiratory uncoupler-sensitive characteristic 99Tc X-ray peak representing 32.0 +/- 2.9 nmoles Tc/mg dry weight, while EPXMA of cytoplasm or nucleus showed no peak significantly greater than the threshold detectability limit of approximately 1 nmole/mg dry weight. Technetium-99 NMR spectroscopy of heart cells equilibrated with 99Tc-SESTAMIBI showed a single peak at -45.5 ppm with no evidence of significant line broadening or chemical shift compared to aqueous chemical standards, indicating that the majority of the complex exists unbound within the mitochondrial matrix. These data quantitatively demonstrate the localization of this lipophilic cationic organometallic complex within mitochondria in situ, consistent with a sequestration mechanism dependent on membrane potentials. Furthermore, this study establishes the general feasibility of combined EPXMA and NMR spectroscopy for the direct subcellular localization and characterization of metallopharmaceuticals, techniques that are readily applicable to MR contrast agents.

Animals↗
PubMed1994

In vivo metabolism of the technetium isonitrile complex [Tc(2-ethoxy-2-methyl-1-isocyanopropane)6]+.

Technetium(2-ethoxy-2-methyl-1-isocyanopropane)6+, [Tc-EIBT] is a complex of technetium(I) structurally similar but slightly more lipophilic than the commercial myocardial perfusion agent Cardiolite [Tc-MIBI]. Tc-EIBI exhibits rapid extraction from the blood into heart, liver, kidney and striated muscle and rapid hepatobiliary clearance. In the guinea pig, unlike Tc-MIBI, this compound is almost completely enzymatically metabolized to numerous cationic complexes containing a mixture of ethyl other and hydroxy isonitrile ligands. Substitution of the ethyl other group for a methyl ether produces an agent that shows selective in vivo metabolism and more rapid clearance from the liver.

Animals↗
PubMed1994

A study of nasal respiratory resistance and craniofacial dimensions in white and West Indian black children.

Two studies have shown that there are morphologic differences in the nasopharynx between the major racial groups. This investigation was conducted to see whether these morphologic differences affected nasal respiration. Twenty-two West Indian and 24 white children (mean age of 13 years 11 months) were studied to examine the relationship between nasorespiratory function and nasopharyngeal and dentofacial structure. The nasorespiratory function was measured in terms of nasal respiratory resistance, NRR, (Pascals/cm3 per second), both by anterior and posterior methods, with a computerized rhinomanometer. Nasopharyngeal structure was described in terms of cephalometric variables. The West Indian cephalometric profile generally conformed to its existing description in the literature including prognathic jaws and bimaxillary proclination; in addition, the West Indians were found to have a greater bony nasopharyngeal width (posterior nasal spine-basion) and shallower nasopharyngeal roof angle (posterior nasal spine-hormion-basion). All rhinomanometric measurements were significantly lower in the West Indian group, especially when posterior rhinomanometry was used. The correlation coefficients between the cephalometric and the rhinomanometric measurements were statistically significant but low. In addition, the measure of mandibular prognathism (angle SNB) was also found to be significantly correlated with the nasorespiratory resistance.

Adolescent↗
PubMed1994

Radiopharmacological evaluation in dogs of a new renal function agent.

The hydrophilic penta-anionic complex [Technetium (Carboxymethylisocyanide)6]-5, [Tc(CNCH2COO-)6]-5 (Tc-CAMI) was synthesized to evaluate its potential as a renal function imaging agent. The compound contains six distally arranged carboxyl groups that can act as substrates for the organic acid receptor of the renal cell to effect tubular secretion of this agent. Dynamic gamma-camera imaging of 99mTc-CAMI was performed in normal dogs to compare its bio-distribution and pharmacokinetics with those of proven tubular secretion (99mTc-MAG3) and globular filtration (99mTc-DTPA) agents. The relative difference between the observed mean renal transit times (MRTT) of 99mTc-CAMI and 99mTc-MAG3 was 0.15 compared with 1.24 for 99mTc-CAMI and 99mTc-DTPA. Pathological models of obstructive uropathy, renal arterial stenosis and renal denervation were produced in the same animals to demonstrate the diagnostic potential of the agent. These experiments and data showing that probenecid competes with 99mTc-CAMI for renal transport indicate that this compound functions as a tubular secretion agent and may be useful for monitoring renal function in various disease states.

Animals↗
PubMed1993

Radiopharmacological studies of 99mTc-CPI: experience with isolated rat atrial tissue.

Extraction, washout and chemical integrity of technetium(I) hexakis (2-carbomethoxy-2-isocyano propane), (99mTc-CPI) were evaluated in isolated contractile rat atrial tissue. 99mTc-CPI accumulated linearly over time at 32 degrees C with uptakes that were both concentration dependent and temperature sensitive. Uptake rates also increased with contractile strength, indicating a dependence of retention on metabolic status of the tissue. Retention indices showed that percent washout of 99mTc-CPI was much slower than control studies with 99mTcO4. HPLC analysis of retained radioactive products in atrial tissue showed most of the activity present as the 99mTc-CPI complex (75%). These observations in isolated rat atrial tissue help explain the interspecies differences in biodistribution of 99mTc-CPI and support the membrane potential dependent model for uptake and retention of technetium isonitrile complexes.

Animals↗
PubMed1993

Tumor uptake of 99mTc-MIBI and 201Tl by a 9L gliosarcoma brain tumor model in rats.

There have been several recent case reports of the accumulation of 99mTc-MIBI [hexakismethoxyisobutylisonitriletechnetium(I), Cardiolite, Sestamibi] in tumors, but no reports of the uptake of this radiopharmaceutical in an animal model. To address this question, the biodistributions of 99mTc-MIBI and 201Tl were compared in Fisher rats bearing 9L gliosarcomas. The results showed that, although the absolute uptake of the tracers by the tumor is relatively low (< 1% ID/g), the tumor-to-normal brain ratios are greater than 6:1 because of low uptake by normal brain. The tumor-to-normal brain ratio of 99mTc-MIBI exceeds that of other currently available 99mTc radiopharmaceuticals suggesting that 99mTc-MIBI may be of particular value in the clinical evaluation of brain tumors and that further investigation of this class of compounds as tumor-avid radiopharmaceuticals is necessary.

Animals↗
PubMed1992

Comparison of neutral and cationic myocardial perfusion agents: characteristics of accumulation in cultured cells.

Uptake and washout kinetics of two new neutral lipophilic technetium-99m-labeled boronic acid adducts of technetium tris(dioxime) (BATO complexes) were studied in monolayers of contractile chick heart cells and compared to the cationic myocardial perfusion agents, 99mTc(CNCH2C(CH3)2OCH3)6+ (Tc-MIBI) and 201Tl+. 99mTcCl(CDOH)2(CDO)(BCH3), where CDO = cyclohexanedione dioxime (CDO-MeB), had a 7-fold greater net accumulation than Tc-MIBI and the most rapid unidirectional washout with a fast initial phase and a slower secondary component. Incubation with cationic membrane transport inhibitors or metabolic inhibitors had little or modest influence, respectively, on uptake of these BATO complexes. Studies with NIH 3T3 fibroblasts indicated that the neutral complexes did not show myocyte specific accumulation.

3T3 Cells↗
PubMed1992

Interspecies variation in biodistribution of technetium (2-carbomethoxy-2-isocyanopropane)6+.

The cationic complex technetium (2-carbomethoxy-2-isocyanopropane)6+ (99mTc-CPI) contains terminal ester groups that were included to provide a pathway for in-vivo metabolism of this compound, thereby enhancing its performance as a myocardial perfusion agent. Biodistribution studies of the compound demonstrated myocardial accumulation in rabbit, guinea pig, and chick, but not in rat and mouse. Radiochemical analysis by HPLC after in-vitro incubation of 99mTc-CPI in blood plasma from the various species confirmed enzymatic hydrolysis to numerous new compounds. Rat and mouse serum produced complete hydrolysis of this agent after incubation for less than 5 sec at 25 degrees C or rates greater than 500 times those observed in human, rabbit, guinea pig and chick serum. Chemical synthesis and isolation of the monohydrolyzed species with subsequent biodistribution studies in guinea pig and rabbit confirmed that this neutral lipophilic complex did not accumulate in heart tissue. It is concluded that varying rates of enzymatic in-vivo hydrolysis produce the interspecies biodistribution differences and may account for the moderate myocardial clearance relative to other isonitrile complexes.

Animals↗
PubMed1992

Subcellular distribution and analysis of technetium-99m-MIBI in isolated perfused rat hearts.

To address the apparent discrepancy between cultured cells and whole heart preparations, Langendorff-perfused rat hearts loaded with hexakis (2-methoxyisobutyl isonitrile) technetium (I) (99mTc-MIBI) were fractionated by a standard differential centrifugation method and fractional contents of 99mTc-MIBI were correlated with the mitochondrial marker, malate dehydrogenase (MDH), and mitochondrial substrates. The "cytosolic" fraction nominally contained 89% +/- 3% of total 99mTc-MIBI, but also contained 91% +/- 1% of total MDH activity by this method. Chromatographic analysis of activity in the "cytosolic" fraction demonstrated greater than 95% of the agent was present as the original free cationic complex; binding to a small molecular weight cytosolic protein was not involved in localization. Addition of the mitochondrial uncoupler CCCP (5 microM) to both "mitochondrial" and "cell fragment" pellets released up to 84% +/- 8% of 99mTc-MIBI content and addition of the mitochondrial substrate succinate (10 microM) in the presence of rotenone (1 microM) enhanced 99mTc-MIBI content by up to 139% +/- 52% over the control. These correlative data from rat hearts indicate that approximately 90% of 99mTc-MIBI activity in vivo is associated with mitochondria in an energy-dependent manner as a free cationic complex, but migrates during fractionation/centrifugation.

Animals↗
PubMed1991

The impact of MMR vaccine on mumps infection in England and Wales.

In the absence of an immunisation programme, epidemics of mumps have occurred at three-yearly intervals in England and Wales. Mumps has been the commonest cause of viral meningitis in children. Routine immunisation (as part of combined measles/mumps/rubella vaccine) was introduced in 1988 and has had a substantial impact on the disease. There has been a 79% reduction in notified cases over two years and the epidemic cycle has been interrupted. Prospects for elimination are good.

Adolescent↗
PubMed1991

Gaining control of the CNS role through written contracts.

Maintaining control of the many aspects of the clinical nurse specialist (CNS) role can be frustrating at times. This article describes the strategy of contract writing to regain control. The following 10 advantages of the method are described. The contract orients staff to the CNS role, formalizes the goal setting process, strengthens relationships, establishes time commitments, serves as a basis for ongoing contracts, sets an evaluation date, furnishes a written record, is a tool for time management, provides a method for conflict management, and provides a mechanism for mutual gain. Examples of a contract and action plan are included.

Contract Services↗
PubMed1991

Characterization of technetium-99m complexes of pentane-2,4-dione bis(N-methylthiosemicarbazone).

Further characterization of the two neutral technetium-99m (99mTc) complexes of pentane-2,4-dione bis-(N-methylthiosemicarbazone) (PETS) was carried out using a new dianionic PETS derivative, 3,3-dimethyl-pentane-2,4-dione bis(N-methylthiosemicarbazone) (DM-PETS), and the well characterized 99mTc complex of 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol (DADT) as references. While PETS generated two neutral 99mTc complexes, 99mTc-PETS-L1 and 99mTc-PETS-L2, by both the stannous reduction method and the ligand exchange reaction with six-coordinated 99mTc(V) complex of N,N'-ethylenebis(acetylacetone imine), DM-PETS formed only one neutral 99mTc complex. 99mTc-PETS-L2, the more lipophilic complex of the two 99mTc-PETS, was obtained with a much higher yield than 99mTc-PETS-L1 by the ligand exchange reaction of PETS with the five-coordinated 99mTc(V) complex of glucoheptonate. In addition, while 99mTc-PETS-L2 and 99mTc-DADT remained unchanged in the presence of CN- anions, a breakdown of the original complexes was observed in 99mTc-PETS-L1 and 99mTc-DM-PETS. All four 99mTc complexes exhibited similar brain, heart and pancreas extraction when injected into mice. These cumulative results imply that 99mTc-PETS-L1 and 99mTc-DM-PETS are six-coordinated mononuclear 99mTc(V) complexes and that 99mTc-PETS-L2 is a five-coordinated mononuclear 99mTc(V) complex. These results also suggest that while the chelate ring structure of the 99mTc-dithiosemicarbazone (DTS) chelate played a significant role in its stability, ionization of the third proton of the PETS molecule and the subsequent resonating structure afforded further stability to the 99mTc-PETS complex. Markedly high lipophilicity of the 99mTc-PETS-L2 may also be explained by assuming that 99mTc-PETS-L2 is the five-coordinated resonating structure.

Animals↗
PubMed1990

Uptake of the cation hexakis(2-methoxyisobutylisonitrile)-technetium-99m by human carcinoma cell lines in vitro.

Uptake of the cationic compound hexakis(2-methoxyisobutylisonitrile)-technetium-99m ([99mTc]MIBI) was examined in nine human tumor cell lines. The concentration of [99mTc]MIBI after a 1-h incubation with the compound varies from 5 to 28% of the activity in the external medium. In contrast, normal V79 cells (Chinese hamster lung fibroblasts) and human peripheral blood mononuclear cells exhibit a minimal uptake of less than 2% of the activity in the medium. Kinetic experiments with SW-13 cells indicate a rapid uptake over time (t1/2 of 10 min) until a steady state is approached whose concentration appears directly correlated with the extracellular concentration of [99mTc]MIBI with no evidence of saturation over the range tested (10(-12)-10(-9) M). [99mTc]MIBI is taken up by a temperature dependent process that is restricted to living cells. Microautoradiography demonstrates that [99mTc]MIBI is clustered in the cytoplasm around the nucleus. Given that depolarizing the plasma membrane potential in high K+ buffer results in lowering the uptake of [99mTc]-MIBI and that alteration of the mitochondrial membrane potential with valinomycin or nigericin induces, respectively, a significant decrease or increase of [99mTc]MIBI uptake, we propose that the plasma and mitochondrial membrane potentials play a major role in the uptake. These data suggest that the gamma emitter [99mTc]MIBI exhibits interesting tumor cell interaction characteristics with promise for in vivo tumor imaging.

Autoradiography↗