Biomedical subjects

T Jones

Publications and source records attributed to T Jones.

At least 145 records · Page 8Linked to original sources

PubMed1998

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: a feasibility study.

PURPOSE: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). METHODS: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. RESULTS: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n = 22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. CONCLUSIONS: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

Acridines↗

PubMed1998

Genomic organization of the segment polarity gene pan in Drosophila melanogaster.

We previously described the molecular cloning of a mammalian T cell factor 1 (TCF-1)-like protein from Drosophila melanogaster, encoded by the pangolin (pan) locus, and demonstrated that it consists of a DNA binding domain similar to that of other high mobility group proteins and a protein-protein interaction domain that binds beta-catenin (Armadillo in Drosophila) but that it lacks a transcriptional activation domain. Here we show that the pan locus spans approximately 50 kb and the mRNA results from the splicing of 13 exons. We note remarkable conservation of the exon/intron boundaries between the human and D. melanogaster genes, suggesting that they share a common ancestor. Chromosomal in situ hybridization locates pan to the base of chromosome 4, near the cubitus interruptus locus. Restriction map and sequence analyses confirm their close proximity. The small fourth chromosome undergoes little or no recombination and was previously reported to lack DNA polymorphisms; however, we note two DNA polymorphisms occurring in three combinations within the pan locus, demonstrating the presence of synonymous substitutions and the past occurrence of recombination. We present evidence suggesting that the protein encoded by pan is more similar to mammalian TCF-1 and Caenorhabditis elegans POP-1 than to mammalian LEF-1.

Amino Acid Sequence↗

PubMed1998

Selection and analysis of rare second-site suppressors of Drosophila RNA polymerase II mutations.

We used a mutagenesis and selection procedure in Drosophila melanogaster to recover rare allele-specific suppressor mutations. More than 11 million flies mutant for one of five recessive-lethal mutations in the two largest subunits of RNA polymerase II were selected for additional mutations that restored viability. Forty-one suppressor mutations were recovered. At least 16 are extragenic, identifying a minimum of three loci, two of which do not map near genes known to encode subunits of RNA polymerase II. At most, 25 are intragenic, 4 reverting the initial altered nucleotide back to wild type. Sequence analysis of interacting mutations in the two largest subunits identified a discrete domain in each subunit. These domains might be contact points for the subunits. Finally, our selections were large enough to allow recovery of multiple independent changes in the same nucleotides yet mutations in other equally likely targets were not recovered. The mutations recovered are not random and might provide insights into possible mechanisms for mutagenesis in eukaryotes.

Alleles↗

PubMed1998

Occupational exposure through spraying remedial pesticides.

A total of 20 surveys at 15 sites of remedial in-situ timber and masonry treatment took place in the latter half of 1996. Two of these surveys concerned wall washes (biocides), the remainder were non-agricultural pesticides. The purpose was to measure the surface deposition and inhalation exposure of the operatives to the pesticide spray fluids used. The diluted spray fluids were found to have significantly different concentrations from those intended by the sprayer. The pesticides were applied at pressures between 320 and 1050 kPa. Deposition rates for spray fluid on coveralls covered a wide range, with more than 30 fold difference between the median and the highest results (median 209 mg/minute; range 27.4 to 6550 mg/min). Contamination of coveralls occurred in all surveys, with the pesticide getting beneath the coveralls in 95% of surveys, with a median 5% contamination beneath the overall. The averaged and normalised deposition pattern was 75% legs, 11% arms, 12% torso and 2% head. Exposure of hands to pesticide (expressed as spray fluid) beneath protective gloves occurred in 89% of surveys (median 5.78 mg/minute; range 0.23 to 358 mg/min) and contamination of socks by spray fluid in 78% of surveys (median 2.08 mg/minute; range 0.12 to 260 mg/min). Exposure by inhalation to spray fluid was measurable in 72% of surveys (median 53.5 mg/m3 TWA; range 4.33 to 1320 mg/m3; 2 data excluded). Inhalation exposure and deposition on coveralls rose markedly at spray pressures above 700 kPa (100 psi).

Agricultural Workers' Diseases↗

PubMed1998

Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris.

BACKGROUND: Preclinical study and human patch tests indicate polyolprepolymer-2 may reduce cutaneous tretinoin-induced irritation. OBJECTIVE: This study compared the clinical efficacy and safety of a 0.025% tretinoin cream containing polyolprepolymer-2 and its vehicle to a commercially-available 0.025% tretinoin cream. METHODS: In this 12-week multicenter, double-blind, parallel group study in patients with mild to moderate acne, objective lesion counts and the investigators' global evaluations evaluated efficacy. Subjective evaluations of skin irritation were used to study safety. RESULTS: A total of 271 patients were enrolled. The active treatments demonstrated comparable efficacy that was statistically significantly greater than that of the vehicle. Safety evaluations of cutaneous and noncutaneous adverse events also indicated comparable results of the active treatments. CONCLUSION: The commercially-available 0.025% tretinoin cream and the 0.025% tretinoin cream containing polyolprepolymer-2 demonstrated comparable efficacy and safety.

Acne Vulgaris↗

PubMed1998

Positron emission tomography (PET) methodology for small animals and its application in radiopharmaceutical preclinical investigation.

The use and usefulness of positron emission tomography (PET) to quantify the specific and selective in vivo binding of radioligands in small laboratory animals is briefly reviewed up to the end of 1996. Emphasis is placed on practical experience with a dedicated, small diameter, tomograph (built in collaboration with CTI, Knoxville, TN), implementing conventional PET methodology.

Animals↗

PubMed1998

Withdrawal of life-support treatment: the experience of critical care nurses.

Technological advances in health care have made it possible to restore and prolong life for patients who would have died in the past. Unfortunately, one consequence of this is that some patients linger in intensive care units (ICUs), dependent on the technologies but with no hope of recovery. Therefore, decisions regarding withdrawal of life-support treatment are increasingly being faced by the health-care team. This study aimed to explore the lived experience of critical care nurses who had cared for patients during withdrawal of life-support. The methodology employed was interpretive phenomenology. Interviews were conducted with seven critical care nurses, with the meanings of the experience of withdrawal of life-support treatment for these nurses extrapolated from the narratives and clustered into themes. The study highlighted the importance of honest communication during the processes of decision-making and withdrawal of treatment. It was important for these nurses to be sure that family members were well-informed regarding the process of withdrawal of life-support treatment and that they could provide support and ensure that the patient's comfort and dignity were maintained during the process. The need to debrief after the event became evident but formal debriefing processes were rarely undertaken.

Adult↗

PubMed1998

Adenocarcinoma of the larynx--a distant metastasis from a rectal primary.

Laryngeal metastases from remote primary tumours are uncommon. They derive mostly from melanomas or renal cell carcinomas. The generally rare laryngeal adenocarcinomas can only be classified as metastatic tumours in the presence of a distant primary of the same histology. Only five cases of a laryngeal secondary originating from adenocarcinoma of the large bowel have been reported in the world literature. A further case is presented which to our knowledge is the first to arise from the rectum, a site which suggests haematogenous tumour spread. This paper emphasizes the need for the search of synchronous metastatic disease and discusses the therapeutic options on the grounds of current management of singular colorectal secondaries.

Adenocarcinoma↗

PubMed1998

Induction of cell death by stimulation of protein kinase C in human epithelial cells expressing a mutant ras oncogene: a potential therapeutic target.

Ras oncogene activation is a key genetic event in several types of human cancer, making its signal pathways an ideal target for novel therapies. We previously showed that expression of mutant ras sensitizes human thyroid epithelial cells to induction of cell death by treatment with phorbol 12-myristate 13-acetate (PMA) and other phorbol esters. We have now investigated further the nature and mechanism of this cell death using both primary and cell line models. The cytotoxic effect of PMA could be blocked by bisindolylmaleimide (GF 109203X), a well-characterized inhibitor of c and n protein kinase C (PKC) isoforms, and by prior down-regulation of PKC, indicating that it is mediated by acute stimulation, rather than down-regulation. Western analysis identified two candidate isoforms--alpha and epsilon--both of which showed PMA-induced subcellular translocation, either or both of which may be necessary for PMA-induced cell death. Immunofluorescence showed that PMA induced a rapid nuclear translocation of p42 MAP kinase of similar magnitude in the presence or absence of mutant ras expression. Cell death exhibited the microscopic features (chromatin condensation, TdT labelling) and DNA fragmentation typical of apoptosis but after a surprising lag (4 days). Taken together with recent models of ras-modulated apoptosis, our data suggest that activation of the MAPK pathway by PMA tips the balance of pro- and anti-apoptotic signals generated by ras in favour of apoptosis. The high frequency of ras mutations in some cancers, such as cancer of the pancreas, which are refractory to conventional chemotherapy, together with the potential for stimulating PKC by cell-permeant pharmacological agents, makes this an attractive therapeutic approach.

Apoptosis↗

PubMed1998

The Checklist of Challenging Behaviour and its relationship with the Psychopathology Inventory for Mentally Retarded Adults.

The Checklist of Challenging Behaviour (CCB) was developed to survey the prevalence of challenging behaviour among people with intellectual disability. It describes 32 behaviours, and data are collected on the frequency, management difficulty and severity of these states. The present paper reports on the relationship between challenging behaviour (as measured by the CCB) and mental health (as measured by the Psychopathology Inventory for Mentally Retarded Adults). In addition, it discusses the differences between the two groups of clients used in the study, i.e. hospital and community subject groups, in terms of challenging behaviour and mental health.

Adult↗

PubMed1998

Expandable anatomical implants in breast reconstructions: a prospective study.

Following success with two-stage anatomical breast reconstructions, we started using expandable anatomical implants for breast reconstruction to achieve one-stage reconstruction. Sixty-three breast reconstructions were carried out with one-stage expandable anatomical implants over a period of 15 months, September 1995 to December 1996. To assess the performance of these implants, 20 patients with mean age 51.1 years (range 34-68 years), who were operated between February 1996 and June 1996, were entered into a prospective study. Overall, very satisfactory results were achieved, with a mean follow-up of 10.1 months (range 8-12 months). Minor complications were recorded in 3 patients and minor secondary adjustment was required in 7 patients.

Adult↗

PubMed1998

Parametric image reconstruction using spectral analysis of PET projection data.

Spectral analysis is a general modelling approach that enables calculation of parametric images from reconstructed tracer kinetic data independent of an assumed compartmental structure. We investigated the validity of applying spectral analysis directly to projection data motivated by the advantages that: (i) the number of reconstructions is reduced by an order of magnitude and (ii) iterative reconstruction becomes practical which may improve signal-to-noise ratio (SNR). A dynamic software phantom with typical 2-[11C]thymidine kinetics was used to compare projection-based and image-based methods and to assess bias-variance trade-offs using iterative expectation maximization (EM) reconstruction. We found that the two approaches are not exactly equivalent due to properties of the non-negative least-squares algorithm. However, the differences are small (< 5%) and mainly affect parameters related to early and late time points on the impulse response function (K1 and, to a lesser extent, VD). The optimal number of EM iteration was 15-30 with up to a two-fold improvement in SNR over filtered back projection. We conclude that projection-based spectral analysis with EM reconstruction yields accurate parametric images with high SNR and has potential application to a wide range of positron emission tomography ligands.

Algorithms↗

PubMed1998

Experience with fully 3D PET and implications for future high-resolution 3D tomographs.

The aim of this paper is to report on experience with 3D positron emission tomography (PET) in our institute where we have three 3D scanners, of which two operate exclusively in 3D mode (ECAT ART, EXACT 3D). Fully 3D PET requires attention to a number of factors which are not as problematic in 2D PET. Firstly, 3D tomographs designed for whole-body acquisition suffer from a large single-photon field of view, extending well beyond the coincidence field of view. Single photons from outside the coincidence field of view increase the dead time and random coincidence rates, and contribute scattered events. For brain studies, we have extended the lead side shielding at the ends of the tomograph to mitigate against these effects, and this has dramatically improved the count rate performance. This approach is not as effective for whole-body scanning. In addition, operating in 3D without septa necessitates new approaches to transmission scanning, as measurements using positron emitters such as 68Ge/68Ga have the unfavourable characteristics of high dead time and high scatter. Both of our fully 3D scanners use 137Cs for single-photon transmission measurements, although the data are treated differently. On the ECAT ART, a combination of physical and electronic collimation effectively reduces transmission scatter to acceptable levels. On the EXACT 3D physical collimation is not as readily implemented and therefore segmentation and reassignment of the histogrammed attenuation (mu) values is employed to produce unbiased attenuation correction factors in 3D. Many of the lessons learnt with these BGO (bismuth germanate) based tomographs will be applicable to the next generation of systems using faster detectors such as lutetium oxyorthosilicate (LSO).

Brain↗

PubMed1998

The effect of activity outside the direct field of view in a 3D-only whole-body positron tomograph.

The ECAT EXACT3D (CTI/Siemens 966) 3D-only PET tomograph has unprecedented sensitivity due to the large BGO (bismuth germanate) detector volume. However, the consequences of a large (23.4 cm) axial field-of-view (FOV) and the need for a patient port diameter to accommodate body scanning make the device more sensitive to photons arising from activity outside the direct (coincidence) FOV. This leads to relatively higher deadtime and an increased registration of random and scatter (true) coincidences. The purpose of this study is to determine the influence of activity outside the FOV on (i) noise-equivalent counts (NEC) and (ii) the performance of a 'model-based' scatter correction algorithm, and to investigate the effect of side shielding additional to that supplied with the tomograph. Annular shielding designed for brain scanning increased the NEC for blood flow (H[2]15O) measurement (integrated over 120 s) by up to 25%. For 11C tracer studies, the increase is less than 5% over 120 min. Purpose-built additional body shielding, made to conform to the shape of a volunteer, reduced the randoms count rate in a heart blood flow measurement (H[2]15O) by about 30%. After scatter correction the discrepancy between ROI count ratios for compartments within the 20 cm diameter 'Utah' phantom differed by less than 5% from true (sampled) activity concentration ratios. This was so with or without activity outside the FOV and with or without additional side shielding. Count rate performance is thus improved by extra shielding but more improvement is seen in head than in body scanning. Measurement of heart blood flow using bolus injections of H(2)15O would benefit from the use of detectors with lower deadtime and superior timing resolution such as LSO (lutetium oxyorthosilicate).

Algorithms↗

PubMed1998

Bone mineral density at distal forearm can identify patients with osteoporosis at spine or femoral neck.

Forearm bone mineral density (BMD) was investigated in women to identify osteoporosis at the spine or femoral neck (or both) defined by WHO criteria (T score -2.5) without requirement for fracture. BMD was measured by single-energy X-ray absorptiometry (DTX100) and by dual-energy X-ray absorptiometry (DXA) in the lumbar spine and femoral neck in 422 subjects aged 22-90 yr. A total of 62% of subjects with osteoporosis (at the spine, femoral neck, or both sites) were detected with 89% specificity [receiver operating characteristics (ROC) analysis] and included all subjects below forearm BMD 0.34 g/cm2. Conversely, above 0.419 g/cm2, only 10% of patients had osteoporosis. A total of 71.8% of women could be assigned either to those who warranted therapy (<0.34 g/cm2) or to those who did not (>0.419 g/cm2) with 90% certainty. Subjects with forearm BMD between 0.34 and 0.419 g/cm2, who constituted 28.2% of the total group and included 31% of subjects with osteoporosis, had a 40% chance of having osteoporosis. This leads to a high identification rate on subsequent DXA scanning, which is thus used efficiently.

Absorptiometry, Photon↗

PubMed1998

Laparoscopic diagnosis of abdominal tuberculosis.

Abdominal tuberculosis (TB) is an uncommon condition in Western societies although Europe and America have noted an increase of this condition in immigrants and AIDS patients. This report documents three diagnosed cases of abdominal TB over a 12-month period in a Melbourne western suburbs teaching hospital which services a large migrant population. We also review the literature on this condition. If migrants present with diffuse abdominal symptoms, the diagnosis of abdominal tuberculosis should always be considered. Laparoscopy should replace diagnostic laparotomy as the definitive diagnostic tool.

Adult↗

PubMed1998

A novel human cytomegalovirus glycoprotein, gpUS9, which promotes cell-to-cell spread in polarized epithelial cells, colocalizes with the cytoskeletal proteins E-cadherin and F-actin.

Processes by which human herpesviruses penetrate and are released from polarized epithelial cells, which have distinct apical and basolateral membrane domains differing in protein and lipid content, are poorly understood. We recently reported that human cytomegalovirus (CMV) mutants with deletions of the gene US9 formed wild-type plaques in cultures of human fibroblasts but were impaired in the capacity for cell-to-cell spread in polarized human retinal pigment epithelial cells. Unlike the glycoproteins that are required for infection, the protein encoded by CMV US9 plays an accessory role by promoting dissemination of virus across cell-cell junctions of polarized epithelial cells. To identify the product and investigate its specialized functions, we selected Madine-Darby canine kidney II (MDCK) epithelial cells that constitutively express CMV US9 or, as a control, US8. The gene products, designated gpUS9 and gpUS8, were glycosylated proteins of comparable molecular masses but differed considerably in intracellular distribution and solubility. Immunofluorescence laser scanning confocal microscopy indicated that, like gpUS8, gpUS9 was present in the endoplasmic reticulum and Golgi compartments of nonpolarized cells. In polarized epithelial cells, gpUS9 also accumulated along lateral membranes, colocalizing with cadherin and actin, and was insoluble in Triton X-100, a property shared with proteins that associate with the cytoskeleton. We hypothesize that gpUS9 may enhance the dissemination of CMV in infected epithelial tissues by associating with the cytoskeletal matrix.

Actins↗

PubMed1998

Otoconia biogenesis, phylogeny, composition and functional attributes.

This work consolidates data about these interesting organic crystals of vertebrate inner ears. It addresses 5 aspects of inner ear otoliths not completely understood to date: 1) embryological data that explains the formation of the crystals, 2) the significance of the organic and the inorganic phase of the otolith and the changing patterns of otoconia formation along the evolutionary tree, 3) otoliths contribution for detecting linear acceleration, 4) the effect that altered gravity and aminoglycosides have on the development and adult shape of the crystals, and the evolutionary significance of a changing shape of the crystals from primitive forms (lamprey) to high vertebrate birds and mammals is discussed, 5) functional attributes of the otolithic organs and morphological modifications of the otoliths by physical and chemical insults are presented with an extensive discussion of the most relevant literature published and available to us.

Animals↗