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K Dixon

Publications and source records attributed to K Dixon.

At least 37 records · Page 2Linked to original sources
PubMed2000

Chromium(VI)-induced mutagenesis in the lungs of big blue transgenic mice.

The mutagenic activity of the hexavalent chromium [Cr(VI)] compound potassium dichromate was examined in the Big Blue transgenic mouse lung, the target organ for Cr(VI) carcinogenesis in humans. Mice were exposed to Cr(VI) by intratracheal instillation of a potassium dichromate (K2Cr2O7) solution. Analysis of the deposition of Cr in mouse lungs revealed that the procedure reproducibly resulted in about 5% retention of the Cr in the lung. Lower but measurable levels were detected in kidney and liver. We found a dose-dependent and time-dependent increase in the mutant frequency in the mouse lung. A significant elevation of the mutant frequency above the spontaneous background was observed two weeks after Cr(VI) intratracheal instillation and at doses above 3 mg/kg. Depletion of tissue glutathione (GSH) levels by buthionine sulfoximine (BSO) before Cr(VI) treatment led to a decrease in the Cr(VI)-induced mutant frequency, compared to that in the animals with normal GSH levels, suggesting a role for GSH in the generation of reactive intermediates during the intracellular reduction of Cr(VI). Sequence analysis for the Cr(VI)-induced mutants revealed a similarity to the spontaneous mutational spectrum observed in mouse lungs, consistent with the generation of oxidative-type DNA damage by Cr(VI). These results demonstrate that Cr(VI) is mutagenic in mouse lung, the target organ for human carcinogenesis.

Animals↗
PubMed1999

Mutational specificity in a shuttle vector replicating in chromium(VI)-treated mammalian cells.

An SV40-based shuttle vector, pZ189, was used to characterize the mutation specificity and to explore the mechanism of chromium mutagenesis in mammalian cells. We showed previously that mutagenic DNA damage is induced by the treatment of plasmid with chromium(VI) plus glutathione in vitro. The induced mutation pattern suggested that chromium mutagenesis can be induced by the generation of reactive oxygen intermediates. To further investigate the mechanism of chromium mutagenesis, we treated cultured mammalian cells containing normal pZ189 vector with chromium(VI). Mutations were induced by Cr(VI) in a dose-dependent manner. The majority of base substitution mutations were widely distributed across the supF mutation target gene and occurred mainly at GC basepairs. Overall, the mutation spectra were not significantly different from each other except for a mutation hot spot at position 43, observed only in plasmids from Cr(VI)-treated cells. The characteristics of Cr(VI)-induced mutations were similar to those observed in the mutation spectra induced by H2O2 treatment of the pZ189 plasmid or plasmid-containing cells. These results are consistent with the hypothesis that induction of mutations by chromium in cultured cells occurs through the generation of oxidative DNA damage.

Animals↗
PubMed1999

The place of bronchoscopic photodynamic therapy in advanced unresectable lung cancer: experience of 100 cases.

OBJECTIVES: The objectives of the study were: (1) to evaluate effectiveness of photodynamic therapy (PDT) for symptom palliation in patients with inoperable lung cancer; (2) to determine survival benefit in a subset of patients. METHODS: One hundred patients, 68 male, 32 female, aged 44-81 years (mean 62.5) with advanced inoperable bronchogenic cancer and endobronchial luminal obstruction were prospectively studied. Eighty-two percent had previous chemo/radiotherapy. The pre-treatment protocol consisted of: clinical, radiological and bronchoscopic examination, pulmonary function testing, assessment of WHO performance status and clinical staging. Treatment protocol was: intravenous injection of 2 mg/kg body weight of photofrin/polyhaematoporphyrin and interstitial illumination using 630 nm laser light 24-72 h later. Follow-up was at 6-8 weeks for 1 year. Then every 3-6 months if applicable. Repeat PDT as necessary. RESULTS: All patients were stage IIIa-IV. The histology of the tumour was: non small cell in 90 and small cell in 10. There was no treatment related mortality. Mean endoluminal obstruction fell from 85.8% to 17.5%, mean forced vital capacity (FVC) and forced expiratory volume in 1s (FEVI) improvement was 430 ml and 280 ml, respectively. Ninety patients died from 6 weeks to 37 months, mean and median survival: 9 months and 5 months, respectively. Ten patients are alive from 13 to 72 months, mean 36 months, median 29 months. Overall 2-year survival was 19%. Multivariant analysis indicated that age, sex, histology and stage of disease did not influence survival significantly but performance status did. Patients with WHO < 2 had mean and median survival of 17.8 and 14 months versus WHO > 2, 6.9 mean and 4 months median survival (log-rank P < 0.0001). CONCLUSIONS: (1) PDT is effective in palliation of inoperable advanced lung cancer. (2) Subset of patients with a better performance status have added survival benefit.

Adult↗
PubMed1998

Dioxin causes a sustained oxidative stress response in the mouse.

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) is the prototype for environmental agonists of the aromatic hydrocarbon receptor (AHR) that are known to produce multiple adverse effects in laboratory animals as well as humans. Although not directly genotoxic, dioxin is known to increase transformation and mutations in mammalian cell culture and to cause an exaggerated oxidative stress response in the female rat. In humans and mice, however, dioxin-mediated oxidative stress appears to be more subtle, causing a response that has been poorly characterized. Using the female C57BL/6J inbred mouse, we show here that intraperitoneal treatment of 5 micrograms TCDD per kilogram on 3 consecutive days produces a striking, prolonged oxidative stress response: hepatic oxidized glutathione levels increase 2-fold within 1 week, and these effects persist for at least 8 weeks despite no further dioxin treatment. Urinary levels of 8-hydroxydeoxyguanosine--a product of DNA base oxidation and subsequent excision repair--remain elevated about 20-fold at 8 weeks after dioxin treatment, consistent with chronic and potentially promutagenic DNA base damage. These results demonstrate that dioxin exposure does produce a sustained oxidative stress response in the mouse.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

The morphological and spectral phenotype of apoptosis in HeLa cells varies following exposure to UV-C and the addition of inhibitors of ICE and CPP32.

Numerous extra- and intracellular factors, including UV radiation, can initiate a programme of cell death by apoptosis. While apoptosis is commonly defined morphologically, the relationships between morphology and molecular events are not well established. To investigate these relationships in HeLa cells, eight morphometric criteria for cell proliferation and damage and 10 criteria for apoptotic phenotype were examined using light microscopy, and corroborated by ultrastructure and spectral imaging. They were identified (1) during a time course after irradiation with 0, 10 or 30 J/m2 UV-C; (2) after separation of apoptotic from normal cells on a Percoll gradient; and (3) after irradiation with UV-C plus perturbation of the apoptotic pathway by treatment with inhibitors of two caspases, ICE and CPP32. The number of cells in apoptosis increased in a dose-dependent manner after UV-C treatment. Centrifugation of irradiated cells on a Percoll gradient increased the collection of apoptotic cells tenfold. The stereotypical apoptotic phenotype, in which cells have deep cytoplasmic blebbing and highly condensed DNA, comprised only a few percent of all apoptosis, and was rarely seen in groups receiving caspase inhibitors. The most common apoptotic phenotype was a rounded cell with large spherical nucleolus and associated DNA. After treatment with UV-C plus inhibitors the apoptotic index was decreased by about 30% compared to UV-C radiation alone. These apoptotic cells had dark spherical cytoplasm with small blebs, greatly increased numbers of cytoplasmic ribosomes, abundant nucleolar material with a large separate granular component, and chromatin condensed at the nuclear membrane. Using the technique of spectral imaging, it was found that the spectrum obtained from the granular component of the nucleolus, which was elevated in apoptotic cells treated with UV-C plus inhibitors, was similar to the dense accumulation of ribosomes in the apoptotic cytoplasm. The data indicate that spectral imaging may be a useful tool for identifying and characterizing variations in the apoptotic process, and that the caspase inhibitors used here do not completely abolish UV-C induced apoptosis, but rather alter its incidence and progression.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Analysis of repair and mutagenesis of chromium-induced DNA damage in yeast, mammalian cells, and transgenic mice.

Chromium (Cr) is a widespread environmental contaminant and a known human carcinogen. We have used shuttle vector systems in yeast, mammalian cells, and transgenic mice to characterize the mutational specificity and premutational DNA damage induced by Cr(VI) and its reduction intermediates in order to elucidate the mechanism by which Cr induces mutations. In the yeast system, treatment of vector-containing cells with Cr(VI) results in a dose-dependent increase in mutations in the SUP4-o target gene of the vector; mutagenesis is enhanced in an apn-1 yeast mutant, deficient in the capacity to repair oxidative-type DNA damage. In vector-containing mammalian cells, treatment with Cr(VI) also results in a dose-dependent increase in mutations in the vector target gene supF. The Cr-induced mutations in supF occurred mostly at G:C base pairs and were widely distributed across the gene, a pattern similar to those observed with ionizing radiation or hydrogen peroxide. These results support the hypothesis that Cr(VI)-induced oxidative-type DNA damage is responsible for Cr mutagenesis in the cell. Recently these studies were extended into the Big Blue transgenic mouse system in which Cr-induced mutagenesis was observed in the lung, the target organ for Cr carcinogenesis in humans. Analysis of the spectrum of these mutations will test whether Cr mutagenesis occurs by similar mechanisms in the intact animal as in cell culture systems and yeast.

Animals↗
PubMed1998

The roles of the behavioral health professional in integrated systems.

It is surprising that integration has only recently re-emerged as a major issue in healthcare. It has taken the economic pressures of managed care and the demands from employers for accountability to place integration in the spotlight. Without these pressures, we would most likely continue to focus our attention in behavioral health on the preservation of traditional professional roles and boundaries, instead of focusing on prevention and developing processes that produce the best outcome for the patient at the lowest possible cost. Integration challenges traditional roles and processes, forcing institutions in our field to change. Role change, as sociologists know, can be profoundly disorienting to individuals and is often vehemently resisted by groups and institutions who have an investment in the status quo. That is where we are now in this field despite our current enthusiasm for this rather innocent-looking concept called integration. We should be confident that the innovators in healthcare will succeed. The economy and quality-of-care concerns demand it. I hope they receive something more than a lukewarm reception.

Behavioral Medicine↗
PubMed1997

Sites of UV-induced phosphorylation of the p34 subunit of replication protein A from HeLa cells.

Exposure of mammalian cells to UV radiation alters gene expression and cell cycle progression; some of these responses may ensure survival or serve as mutation-avoidance mechanisms, lessening the consequences of UV-induced DNA damage. We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. To characterize further the role of RPA hyperphosphorylation in the cellular response to UV irradiation and to determine which protein kinases might be involved, we identified by phosphopeptide analysis the sites phosphorylated in the p34 subunit of RPA (RPA-p34) from HeLa cells before and after exposure to 30 J/m2 UV light. In unirradiated HeLa cells, RPA-p34 is phosphorylated primarily at Ser-23 and Ser-29. At least four of the eight serines and one threonine in the N-terminal 33 residues of RPA-p34 can become phosphorylated after UV irradiation. Two of these sites (Ser-23 and Ser-29) are known to be sites phosphorylated by Cdc2 kinase; two others (Thr-21 and Ser-33) are consensus sites for the DNA-dependent protein kinase (DNA-PK); the fifth site (Ser-11, -12, or -13) does not correspond to the (Ser/Thr)-Gln DNA-PK consensus. All five can be phosphorylated in vitro by incubating purified RPA with purified DNA-PK. Two additional sites, probably Ser-4 and Ser-8, are phosphorylated in vivo after UV irradiation and in vitro by purified DNA-PK. The capacity of purified DNA-PK to phosphorylate many of these same sites on RPA-p34 in vitro implicates DNA-PK or a kinase with similar specificity in the UV-induced hyperphosphorylation of RPA in vivo.

Amino Acid Sequence↗
PubMed1997

Total quality management in accredited New South Wales hospitals: a public/private comparison.

Analysis of data collected in a 1994-95 survey of accredited New South Wales hospitals examined the adoption of key elements of total quality management practice in the public and private sectors. In a number of areas of practice widely considered to be central to a hospital's total quality management efforts, there was no statistically significant difference between the two sectors. Where differences existed, total quality management practices more likely to be adopted by public hospitals were limited in their scope and likely to be explained by structural peculiarities. In contrast, private hospitals were more likely to adopt practices more critical to the successful implementation of total quality management.

Accreditation↗
PubMed1997

Endoscopic laser therapy in malignant tracheobronchial obstruction using sequential Nd YAG laser and photodynamic therapy.

BACKGROUND: Because the survival after treatment of advanced inoperable endo-tracheobronchial carcinoma is so poor, a pilot study was undertaken to evaluate the combined cumulative effect on survival of neodymium yttrium aluminium garnet (Nd YAG) laser followed by photodynamic treatment used endoscopically. METHODS: Seventeen patients who presented between January 1992 and March 1996 with inoperable tracheobronchial lesions causing more than 50% endoluminal obstruction were selected to enter the pilot study. Initially they had bronchoscopic Nd YAG laser treatment to debulk the tumour, and this was followed six weeks later by photodynamic therapy to treat the residual tumour. RESULTS: All patients had symptomatic relief and at least a partial response, and seven had a complete response for 3-6 months. Eight of the 17 (47%) survived for at least two years and 11 (65%) survived for a year or more. The median survival of the 10 patients who had died by the time of writing was 18.5 months (range 5-39), 95% confidence interval (CI) 9.9 to 29.5. CONCLUSIONS: Combined Nd YAG laser and endoscopic photodynamic therapy may be an effective palliative treatment for patients with inoperable endotracheobronchial cancer.

Aged↗
PubMed1997

A prospective study of changes in negative mood states of women undergoing surgical hysterectomy: the relationship to cognitive predisposition and familial support.

Levels of anxiety and depression were documented by questionnaire response from a sample of 89 women who were to undergo surgical hysterectomy 3 weeks later. Fifty-four per cent (n = 48) of the sample reported anxiety and 26% (n = 23) reported depression at clinical levels during the preoperative period, with an additional number (n = 16 anxiety; n = 19 depression) at borderline status. Despite an overall significant postoperative reduction of negative mood states, clinical levels of anxiety were found in a substantial minority of women both 2 (24%) and 6 months (31%) after surgery. Levels of depression at these times were respectively 13% and 11% of the sample which provided postoperative information. These data confirm previous reports of high levels of negative mood states in patients referred for surgical hysterectomy. However, analyses of individual profiles of change confirm that there was a beneficial outcome for the large majority of the women, with 83% of those with clinical levels of anxiety showing improved status. Regression analyses indicated that postoperative outcomes with respect to negative affect could be predicted from preoperative status, and the data provide some support for the hypothesis that for a minority of women, negative mood states co-presented with gynecological symptoms may not be attenuated by surgery. Both dispositional resilience and familial cohesiveness were entered as significant variables in regression models examining postoperative status, although they provided only a limited increase to the postoperative variance prediction from measure of preoperative levels of affect. Preoperative mood status was found to be inversely related to an intrapersonal dimension of 'dispositional resilience' and to 'family cohesiveness'. It is suggested that measurement of preoperative mood status to family cohesiveness and dispositional resilience may provide useful adjunctive measures in attempts to identify women at risk of reporting an unsatisfactory surgical outcome.

Adult↗
PubMed1997

The reliability of the items of the Functional Assessment Measure (FAM): differences in abstractness between FAM items.

The reliability of the Functional Assessment Measure (FIM+FAM) is an important issue with its increased use in the measurement of neurological disability and rehabilitation outcome. Although the Motor items have good reliability ratings, the Cognitive items are more difficult to complete and their reliability is not as good. This study tests the suggestion that this might be due to the Cognitive items being more abstract. A keyword from each of four Motor items was compared with a keyword from four Cognitive items. Abstractness was measured by measuring the 'imageability' of each keyword. The Motor items were found to have a significantly higher mean imageability rating than the Cognitive items. Thus, there is support for the suggestion that abstractness contributes to the poorer reliability of the Cognitive items. These results led to the proposal that the reliability of the Cognitive items might be improved by various methods of increasing the tangibility of these measures (e.g. subdivision of broad categories of disabilities, enhancing item descriptions, training raters to increase their recognition of relevant observations, and using specific assessment tasks to elicit relevant behaviours).

Activities of Daily Living↗
PubMed1997

Improving public/private partnership in managed behavioral healthcare.

This paper is the second version of a working document developed to explore opportunities and difficulties in the national shift to managed care in the public sector. Leaders in the public and private sectors continue their collaboration in contributing new models of integration that preserve the best of the public system but challenge the field to combine social mission with good business practice. The first version was developed by the American Managed Behavioral Healthcare Association and the National Association of State Mental Health Program Directors. This document, developed by AMBHA, NASMHPD, the National Association of County Behavioral Health Directors, and the National Council of Community Mental Health Centers, expands on the first white paper, published here in October 1995, and is based on developing issues and concerns in public sector managed behavioral healthcare. This paper is not intended to represent prescriptive standards but rather to articulate "best practice" in an area that continually changes as public payors privatize significantly larger portions of public mental health. In April 1996, Behavioral Healthcare Tomorrow published a response from the consumer advocacy perspective, and the ideas presented in this paper remain open to input and discussion.

Delivery of Health Care, Integrated↗
PubMed1996

Complete replication of plasmid DNA containing a single UV-induced lesion in human cell extracts.

To investigate the effect of the major UV-induced lesions on SV40 origin-dependent DNA replication and mutagenesis in a mammalian cell extract, double-stranded plasmids containing a single cis,syn-cyclobutane dimer or a pyrimidine-pyrimidone (6-4) photoproduct at a unique TT sequence have been constructed. These plasmids have been used as templates in DNA replication-competent extracts from human HeLa cells. Plasmids containing a single pyrimidine cyclobutane dimer on the potential lagging strand for DNA replication are replicated with an efficiency approximately equal to that of an unmodified plasmid. A small decrease in replication efficiency of approximately 20% was observed when the lesion was located on the potential leading strand for DNA replication. In both orientations, DpnI-resistant, replicated closed circular plasmid DNA was sensitive to nicking by the pyrimidine dimer-specific enzyme, T4 endonuclease V, indicating that complete replication of the damaged plasmid occurs in vitro. In contrast, a (6-4) photoproduct, within the same site and sequence context on the lagging strand for DNA synthesis, inhibits replication in vitro by an average of approximately 50%, indicating that the mammalian replication complex responds differently to the two major UV-induced lesions during DNA replication in vitro. Analysis of the DpnI-resistant, replicated DNA for mutations targeted to the lesion site indicates that neither of these lesions resulted in significant mutagenesis. UV-induced lesions at TT sites may therefore be poorly mutagenic under these conditions for DNA replication in human cell extracts in vitro.

Base Sequence↗
PubMed1996

Induction of mutagenic DNA damage by chromium (VI) and glutathione.

Certain chromium (Cr) compounds are known to be carcinogenic in humans and mutagenic in cell culture. However, the mechanism of Cr mutagenesis is not well understood. It appears that intracellular reduction of Cr by agents such as glutathione plays a role in the induction of DNA damage. We have used a simian virus 40-based shuttle vector to investigate the relationship between chromium-induced DNA damage and Cr mutagenicity. The treatment of the plasmid pZ189 with Cr(VI) plus glutathione (GSH) induced DNA strand breaks and reduced the plasmid biological activity, whereas Cr(III) treatment with or without GSH did not give rise to such DNA damage. When Cr(VI)/GSH- or Cr(III)/GSH-treated pZ189 was replicated in mammalian cells, a dose-dependent increase in mutant frequency was observed with Cr(VI)/GSH-treated pZ189, but not with Cr(III)/GSH-treated plasmid. About 43% of the mutants from Cr(VI)/GSH-treated pZ189 were deletion mutants. The remainder were base substitution mutants, mostly GC-->AT transitions and GC-->TA transversions. This pattern of mutagenesis is similar to that observed with other agents that cause oxidative DNA damage such as ionizing radiation and H2O2. These results support the hypothesis that Cr mutagenesis can be induced by the generation of reactive oxygen intermediates during the reduction of Cr(VI) by glutathione.

Animals↗
PubMed1996

Breathing retraining: a three-year follow-up study of treatment for hyperventilation syndrome and associated functional cardiac symptoms.

This study was designed to evaluate the long-term effects of paced diaphragmatic breathing on subjects who reported functional cardiac symptoms and who also demonstrated associated signs of hyperventilation syndrome. Subjects were a representative sample composed of 10 out of the original 41 subjects who had participated three years previously in a study designed to evaluate the short-term effects of breathing retraining on functional cardiac symptoms and respiratory parameters (respiratory rate and end-tidal carbon dioxide). The results of this follow-up study indicate that breathing retraining had lasting effects on both respiratory parameters measured. Subjects evidenced significantly higher end-tidal carbon dioxide levels and lower respiratory rates when compared to pretreatment levels measured three years earlier. Subjects also continued to report a decrease in the frequency of functional cardiac symptoms when compared to pretreatment levels. We conclude that breathing retraining has lasting effects on respiratory physiology and is highly correlated with a reduction in reported functional cardiac symptoms.

Female↗