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Biomedical subjects

K Dixon

Publications and source records attributed to K Dixon.

At least 55 records · Page 3Linked to original sources
PubMed1996

Endoscopic laser treatment for tracheal obstruction.

OBJECTIVE: To evaluate the efficacy of endoscopic laser treatment (ELT) in patients with endoluminal tracheal obstruction. METHOD: A neodymium: yttrium aluminium, garnet (Nd:YAG) laser was used on 60 patients with significant (> 50%) tracheal stenosis. They were grouped as follows: primary tracheal malignancy (PTM n = 11), secondary tracheal malignancy (STM n = 27), benign tracheal tumours (BTT n = 4) and inflammatory tracheal stenosis (ITS n = 18). Assessment was made clinically, endoscopically and using ventilatory function tests (forced vital capacity (FVC) and peak expiratory flow rate (PEFR)), before and after treatment. RESULTS: There was no treatment-related mortality. Peak expiratory flow rate improved significantly overall and in the PTM, STM and ITS groups. There was no significant improvement in FVC overall or in any of the individual groups. Subjectively, 98% of the patients felt improved by ELT. The survival in each group was: in the PTM group three patients are alive at 36, 49 and 74 months while all other patients died, giving a mean survival of 8.8 +/- 2.6 months. In the STM group the mean survival was 4.7 +/- 4.2 months. In the BTT group all patients are alive at the time of writing, two require regular ELT. In the ITS group three patients died, two required Montgomery tracheostomy tubes for tracheomalacia, seven are receiving regular ELT and six are disease free at the time of writing. CONCLUSION: We conclude that ELT is an effective method for the palliation of malignancy which occasionally gives long-term survival. It has a place in the management of benign tracheal neoplasia and inflammatory stenosis with a potential for cure in these cases.

Actuarial Analysis↗
PubMed1996

Total quality management practices in the NSW hospital system--an overview.

A two-phase descriptive study involving a questionnaire survey was undertaken during 1994 and 1995 to evaluate the extent of implementation of total quality management practices in New South Wales hospitals accredited by the Australian Council on Healthcare Standards. A survey response rate of 72 per cent was attained. Results indicated that most hospitals were aware of and consciously implemented aspects of the total quality management philosophy in some way. There is little evidence that whole systems have embraced the total quality management approach as a fully integrated endeavour.

Community-Institutional Relations↗
PubMed1996

Cell proliferation and nuclear abnormalities are increased and apoptosis is decreased in the epidermis of the p53 null mouse after topical application of benzo[a]pyrene.

Cell proliferation and cell death in mouse epidermis are altered by topical application of benzo[a]pyrene (BaP), a procarcinogen, which yields metabolites that can form DNA adducts. The mitotic rate, nuclear abnormalities, labelling index, grain density, necrosis and apoptosis were compared in the epidermis of TSG-p53 null (p53-/-) and C57BL wild-type (wt) mice after weekly treatments with BaP to determine whether the absence of the p53 gene altered cytokinetic responses to DNA damaging agents in vivo. Acetone alone or 64 micrograms BaP in 50 microliters acetone was applied to the clipped dorsum of mice once, or in four consecutive weekly treatments. Indices of cell proliferation and cell death were the same in both wt and p53-/- mice treated only with acetone. One application of BaP depressed mitosis and slowed the rate of DNA synthesis in both genotypes. After four applications of BaP the number of keratinocytes in S phase increased substantially, while there was no further slowing in the rate of S phase in the wt and p53-/- mice. Cell proliferation rates and numbers of cells with nuclear abnormalities were higher and there were fewer apoptotic cells and apoptotic bodies in the p53-/- mice than in the wt mice. Numbers of 'sunburn' cells were similar in both types.

Acetone↗
PubMed1996

Isolated liver perfusion for liver metastases: pharmacokinetic advantage?

The pharmacokinetic advantage of a novel system to noninvasively isolate the hepatic venous outflow and infuse high doses of chemotherapy (doxorubicin or 5-FU) is discussed and compared with intravenous infusion and intra-arterial infusion without hepatic venous detoxification. This dose intensification schema may provide new pharmacokinetic and pharmacodynamic principles for the treatment of a variety of tumors metastasizing the liver, including melanoma, sarcoma, and adenocarcinoma.

Adenocarcinoma↗
PubMed1995

Comparison of the responses of human melanocytes with different melanin contents to ultraviolet B irradiation.

Melanin is thought to serve in photoprotection. To investigate this, we have compared the responses of cultured human melanocytes derived from different pigmentary phenotypes (skin types I-VI) to a single irradiation with different doses of UVB light, ranging between 11.7 and 70.1 mJ/cm2. After UVB irradiation, heavily pigmented melanocytes had the same percent survival but a greater capacity to resume proliferation than their lightly pigmented counterparts. A significant increase in melanin content was observed in heavily pigmented but not in lightly pigmented melanocytes. Irradiation with UVB light blocked melanocytes, regardless of their melanin content, in G1, and induced the expression of the tumor suppressor p53 protein within 4 h. This induction steadily increased up to 48 h in lightly pigmented melanocytes; however, in heavily pigmented melanocytes, p53 level peaked at 24 h after UVB treatment and declined thereafter. Additionally, DNA from lightly pigmented melanocytes contained significantly higher numbers of cyclobutane pyrimidine dimers than did DNA from heavily pigmented melanocytes after irradiation with increasing doses of UVB light. We speculate that the prolonged induction of p53 in lightly pigmented melanocytes arrests them in G1 for a long time period in order to repair extensive DNA damage. The above described differences might partially explain the increased susceptibility of individuals with lightly pigmented skin compared to individuals with dark skin to the photodamaging and photocarcinogenic effects of sun exposure.

Cell Cycle↗
PubMed1995

Analysis of mutations induced by replication of UV-damaged plasmid DNA in HeLa cell extracts.

We have used an SV40-based shuttle vector, pZ189, to investigate the capacity of HeLa cell extracts to reproduce the in vivo process of mutation fixation. We showed previously that when UV-irradiated pZ189 is replicated in these extracts, bypass of UV photoproducts occurs, resulting in base substitution mutations in the supF gene of the vector. Here we report the DNA sequence characterization of a collection of 60 of these UV-induced mutants. Most of the mutations observed are single or tandem double base substitutions at dipyrimidine sites; of these, approximately 90% are G:C-->A:T transitions. Mutations are observed predominantly at a few sites, in particular at positions 155 and 156 in the supF sequence. No dramatic differences in the mutation spectrum were observed when the orientation of the supF gene was reversed with respect to the SV40 origin of replication, suggesting that mutation fixation occurs similarly on both the leading and the lagging strands for DNA replication. Generally, the mutational hot spots observed in vitro are at the same sites as those observed when UV-irradiated pZ189 was passaged in human or monkey cells in culture. Thus, it appears that the replication and mutagenesis of UV-damaged templates in HeLa cell extracts accurately reflects these processes in the intact cell.

Base Sequence↗
PubMed1995

Analysis of mutagenesis in UV-sensitive mouse lymphoma L5178Y-R cells with a polyomavirus-based shuttle vector.

A newly-developed polyomavirus-based shuttle vector, pPySLPT-2, was used to analyze mutations induced by UV radiation in the two related mouse lymphoma cell lines, L5178Y-R (LY-R) and L5178Y-S (LY-S). These well-studied cell lines differ in sensitivity to UV radiation, apparently due to differences in DNA repair capacity. Consistent with these differences, we found that replication of UV-irradiated vector is inhibited to a greater extent in the UV sensitive LY-R cells than in the LY-S cells. Mutations were induced in the vector's supF target gene at a higher frequency in the LY-R cells than in the LY-S cells, but the sequence characteristics of the base substitution mutations were similar in the two cell lines. The pattern of UV-induced mutations in the supF target gene of this polyomavirus-based vector, replicated in the mouse cells, was very similar to the pattern observed in the same target gene in the analogous simian virus 40-based vector, pZ189, replicated in monkey and human cells.

Animals↗
PubMed1995

A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development.

The exquisite sensitivity of thymocytes to steroid-induced apoptosis, the steroidogenic potential of thymic epithelial cells, and the ability of steroid synthesis inhibitors to enhance antigen-specific deletion of thymocytes in fetal thymic organ cultures suggest a role for glucocorticoids in thymocyte development. To address this further, transgenic mice that express antisense transcripts to the glucocorticoid receptor (GR) specifically in immature thymocytes were generated. The consequent hyporesponsiveness of thymocytes to glucocorticoids was accompanied by a reduction in thymic size, primarily owing to a decrease in the number of CD4+CD8+ cells. While an enhanced susceptibility to T cell receptor (TCR)-mediated apoptosis appeared to be partially responsible for this reduction, thymocyte loss could also be detected before thymocytes progressed to the CD4+CD8+ TCR alpha beta-expressing stage. These results suggest that glucocorticoids are necessary for survival and maturation of thymocytes, and are consistent with a role for steroids in both the transition from CD4-CD8- to CD4+CD8+ cells and the survival of CD4+CD8+ cells stimulated via the TCR.

Animals↗
PubMed1995

Spontaneous haemopneumothorax: a surgical emergency.

We describe two cases of spontaneous haemopneumothorax treated successfully at emergency thoracotomy. We emphasize the importance of torn apical vascular adhesions as a source of intrathoracic haemorrhage in these two cases.

Adult↗
PubMed1994

UV light-induced DNA synthesis arrest in HeLa cells is associated with changes in phosphorylation of human single-stranded DNA-binding protein.

We show that DNA replication activity in extracts of human HeLa cells decreases following UV irradiation. Alterations in replication activity in vitro parallel the UV-induced block in cell cycle progression of these cells in culture. UV irradiation also induces specific changes in the pattern of phosphorylation of the 34 kDa subunit of a DNA replication protein, human single-stranded DNA-binding protein (hSSB). The appearance of a hyperphosphorylated form of hSSB correlates with reduced in vitro DNA replication activity in extracts of UV-irradiated cells. Replication activity can be restored to these extracts in vitro by addition of purified hSSB. These results suggest that UV-induced DNA synthesis arrest may be mediated in part through phosphorylation-related alterations in the activity of hSSB, an essential component of the DNA replication apparatus.

Cell Cycle↗
PubMed1994

Anorectic responses to dietary amino acid imbalance: effects of vagotomy and tropisetron.

We investigated the roles of the vagus nerve and the serotonin3 (5-HT3) receptor in mediating the food intake depression associated with amino acid deficiency. The food intake of sham-operated (sham) rats given an isoleucine-imbalanced (IMB) diet was reduced to < 40% of control basal (BAS) diet intake (P = 0.0009), and pretreatment with the 5-HT3 antagonist tropisetron (Trop) increased IMB intake by twofold over the vehicle (VEH)-treated group (P < or = 0.0001), as we have reported before. However, after subdiaphragmatic vagotomy (VAGX), IMB intake was increased to a level intermediate between the sham-VEH and sham-Trop groups, while administration of Trop did not increase IMB intake over VAGX alone. By the end of day 1, the VAGX-Trop group had eaten only 1 g more of IMB than the VAGX-VEH group (NS). We conclude that 1) the vagus is among the physiological systems involved in the anorectic responses to IMB and 2) intact vagal function is necessary for the full effect of 5-HT3 antagonists in alleviating the anorectic responses to IMB.

Animals↗
PubMed1993

Replication and mutagenesis of UV-damaged DNA templates in human and monkey cell extracts.

We have used in vitro DNA replication systems from human HeLa cells and monkey CV-1 cells to replicate a UV-damaged simian virus 40-based shuttle vector plasmid, pZ189. We found that replication of the plasmid was inhibited in a UV fluence-dependent manner, but even at UV fluences which caused damage to essentially all of the plasmid molecules some molecules became completely replicated. This replication was accompanied by an increase (up to 15-fold) in the frequency of mutations detected in the supF gene of the plasmid. These mutations were predominantly G:C-->A:T transitions similar to those observed in vivo. Treatment of the UV-irradiated plasmid DNA with Escherichia coli photolyase to reverse pyrimidine cyclobutane dimers (the predominant UV-induced photoproduct) before replication prevented the UV-induced inhibition of replication and reduced the frequency of mutations in supF to background levels. Therefore, the presence of pyrimidine cyclobutane dimers in the plasmid template appears to be responsible for both inhibition of replication and mutation induction. Further analysis of the replication of the UV-damaged plasmid revealed that closed circular replication products were sensitive to T4 endonuclease V (a pyrimidine cyclobutane dimer-specific endonuclease) and that this sensitivity was abolished by treatment of the replicated DNA with E. coli photolyase after replication but before T4 endonuclease treatment. These results demonstrate that these closed circular replication products contain pyrimidine cyclobutane dimers. Density labeling experiments revealed that the majority of plasmid DNA synthesized in vitro in the presence of bromodeoxyuridine triphosphate was hybrid density whether or not the plasmid was treated with UV radiation before replication; therefore, replication of UV-damaged templates appears to occur by the normal semiconservative mechanism. All of these data suggest that replication of UV-damaged templates occurs in vitro as it does in vivo and that this replication results in mutation fixation.

Animals↗
PubMed1992

SV40 small t deletion mutants preferentially transform mononuclear phagocytes and B lymphocytes in vivo.

Hamsters injected intracardiacally with wild-type SV40 developed diverse tumors, with no one type predominating. However, hamsters injected with small t deletion mutants of SV40 uniformly developed true histiocytic or B-cell lymphomas, both of which arise from rapidly dividing cell populations, with very few tumors of other types. Our results are consistent with in vitro studies which suggest a requirement for the small t function in SV40 transformation of nondividing cells.

Animals↗
PubMed1992

HeLa cell single-stranded DNA-binding protein increases the accuracy of DNA synthesis by DNA polymerase alpha in vitro.

To determine whether cellular replication factors can influence the fidelity of DNA replication, the effect of HeLa cell single-stranded DNA-binding protein (SSB) on the accuracy of DNA replication by HeLa cell DNA polymerase alpha has been examined. An in vitro gap-filling assay, in which the single-stranded gap contains the supF target gene, was used to measure mutagenesis. Addition of SSB to the in vitro DNA synthesis reaction increased the accuracy of DNA polymerase alpha by 2- to 8-fold. Analysis of the products of DNA synthesis indicated that SSB reduces pausing by the polymerase at specific sites in the single-stranded supF template. Sequence analysis of the types of errors resulting from synthesis in the absence or presence of SSB reveals that, while the errors are primarily base substitutions under both conditions, SSB reduces the number of errors found at 3 hotspots in the supF gene. Thus, a cellular replication factor (SSB) can influence the fidelity of a mammalian DNA polymerase in vitro, suggesting that the high accuracy of cellular DNA replication may be determined in part by the interaction between replication factors, DNA polymerase and the DNA template in the replication complex.

Bacterial Proteins↗
PubMed1992

Simian virus 40 (SV40) small t antigen inhibits SV40 DNA replication in vitro.

We describe a biochemical function of simian virus 40 small t antigen, the inhibition of simian virus 40 large T antigen-mediated viral DNA replication in an in vitro replication system. Our results suggest that in this system, small t antigen prevents protein phosphatase 2A-mediated activation of large T antigen.

Antigens, Polyomavirus Transforming↗
PubMed1991

Genetic variation of the glucocorticoid receptor from a steroid-resistant primate.

The neotropical cotton-top marmoset (Saguinus oedipus) is a New World primate known to have markedly increased total and free plasma cortisol concentrations when compared with Old World primates including man. The relative end-organ 'resistance' to glucocorticoids found in various New World primates has been attributed to a glucocorticoid receptor (GR) with diminished affinity for glucocorticoids. It has been demonstrated that the marmoset GR has approximately tenfold lower binding affinity for dexamethasone when compared with the human GR. We have examined the primary structure of the marmoset GR by molecular cloning and sequencing of GR functional domains. A library of cDNA clones was constructed in the phage vector gamma gt10 using poly(A)+ RNA from a marmoset-derived lymphoid cell line, and screened using the human GR cDNA. DNA sequencing determined 76 individual nucleotide substitutions in the coding region of the marmoset GR. Comparison of the marmoset GR nucleotide sequence with the human GR cDNA coding region indicated an overall sequence homology of about 97%. Thirty of the nucleotide substitutions lead to alterations in the predicted amino acid sequence (28 amino acid substitutions) of the marmoset GR. The size of the marmoset GR predicted from the 778 amino acids is approximately 90,000 which is in agreement with previous size estimates of the human and marmoset GRs. Alterations of amino acid sequence in the marmoset GR were greatest towards the amino terminus, including the tau 1 domain putatively involved in transcriptional activation. The DNA-binding domain contained an additional codon (arginine).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗