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D Bowen

Publications and source records attributed to D Bowen.

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

A genomic sample sequence of the entomopathogenic bacterium Photorhabdus luminescens W14: potential implications for virulence.

Photorhabdus luminescens is a pathogenic bacterium that lives in the guts of insect-pathogenic nematodes. After invasion of an insect host by a nematode, bacteria are released from the nematode gut and help kill the insect, in which both the bacteria and the nematodes subsequently replicate. However, the bacterial virulence factors associated with this "symbiosis of pathogens" remain largely obscure. In order to identify genes encoding potential virulence factors, we performed approximately 2,000 random sequencing reads from a P. luminescens W14 genomic library. We then compared the sequences obtained to sequences in existing gene databases and to the Escherichia coli K-12 genome sequence. Here we describe the different classes of potential virulence factors found. These factors include genes that putatively encode Tc insecticidal toxin complexes, Rtx-like toxins, proteases and lipases, colicin and pyocins, and various antibiotics. They also include a diverse array of secretion (e.g., type III), iron uptake, and lipopolysaccharide production systems. We speculate on the potential functions of each of these gene classes in insect infection and also examine the extent to which the invertebrate pathogen P. luminescens shares potential antivertebrate virulence factors. The implications for understanding both the biology of this insect pathogen and links between the evolution of vertebrate virulence factors and the evolution of invertebrate virulence factors are discussed.

Animals↗
PubMed2000

Interaction energy analyses of folate analog binding to human dihydrofolate reductase: contribution of the antifolate substructural regions to complex stability.

The three-dimensional structure of the human dihydrofolate reductase (DHFR), methotrexate tetrazole, and NADPH ternary complex was used to model the corresponding ternary complexes with methotrexate tetrazole replaced by methotrexate, methotrexate-polyglutamate with three glutamyl residues, and 5,10-deazaaminopterin, respectively. Each complex was solvated in a 60-angstrom cube of explicit water and subjected to structural minimization followed by interaction energy analyses. Interaction energy calculations were performed for the antifolate interaction with water, NADPH, the DHFR binding site residues, the entire DHFR protein, and the solvated NADPH:DHFR complex. These studies revealed that methotrexate-polyglutamate exhibited the most stable interactions and that approximately one half of antifolate:DHFR stability could be accounted for by the interaction of the antifolate with the binding site residues. The antifolate structures were also subdivided into heterocyclic, phenyl, and glutamyl substructural regions. Interaction energies were subsequently calculated for the interactions of the subregions with water, NADPH, the DHFR binding site residues, the DHFR protein, and the solvated NADPH:DHFR complex. The glutamyl substructural region showed the greatest contribution to overall antifolate binding stability due to its interaction with the DHFR protein. The heterocyclic and phenyl substructural regions generally showed much less stable interactions. These results suggest that the primary stabilizing factor of the antifolate interaction is the interaction of glutamyl with the DHFR protein. Additionally, interaction energy analyses were performed for specific groups of atoms within the substructural regions. These studies indicated that the stability of the glutamyl interaction is due to the interaction of glutamyl oxygen atoms with the DHFR protein. In the case of the methotrexate tetrazole complex, the tetrazole nitrogens also contribute significantly to the stability of the glutamyl interaction. The carbon atoms of the heterocyclic and phenyl groups both showed more stable interactions with NADPH than with water, while the nitrogen atoms showed more stable interactions with water than with NADPH. Collectively, these results indicate that the glutamyl region is the most important in antifolate binding stability.

Aminopterin↗
PubMed2000

Implications for improved high-dose methotrexate therapeutic effects in cultured human breast cancer and bone marrow cells.

The cytotoxicity of high-dose methotrexate (MTX), 10 and 100 microM, and 5-fluorouracil (5-FU) combinations is independent of sequence in human MDA-MB-436 breast carcinoma cells. The growth inhibitory effects of 10 and 100 microM MTX are 22.54+/-1.56% and 16.20+/-0.74%, respectively, of the control rate. When the MTX and 5-FU concentrations are 10 microM, antiproliferative effects of MTX 2 hr before 5-FU (MTX/5-FU) and 5-FU 2 h before MTX (5-FU/MTX) are 25.17+/-1.23% and 25.60+/-1.28% of the control rate, respectively. The percentage of control rates for 5-FU alone is 94.89+/-1.35%. The growth rates of MDA-MB-436 cells in 100 microM MTX and 10 microM 5-FU are 15.19+/-0.62% (MTX/5-FU) and 16.53+/-0.85% (5-FU/MTX) of the control rate. The growth of cancer cells in the presence of 5-FU alone is 93.82+/-1.69% of the control rate. A comparison of the cell-killing effects of MTX and the nonpolyglutamable antifolate trimetrexate (TMQ) alone and in combination with 5-FU was performed to indirectly explore the role of polyglutamylation in breast cancer and bone marrow cells. The comparisons were made in equitoxic concentrations (10 microM) of MTX and TMQ and the time of exposure was the same. The inhibitory effects of TMQ, TMQ/5-FU, and 5-FU/TMQ in breast cancer cells were identical, but significantly less than MTX, MTX/5-FU, and 5-FU/MTX. The interaction between TMQ and MTX, TMQ/5-FU and MTX/5-FU, and 5-FU/TMQ and 5-FU/MTX was quantitatively similar in bone marrow. (Significant protection occurred in bone marrow cells exposed to 5-FU/TMQ and 5-FU/MTX.) Because the effects of 5-FU/MTX and 5-FU/TMQ on bone marrow were the same, it is unlikely that polyglutamylation plays a significant role in the protective effects of 5-FU. However, the greater inhibitory effect of MTX or MTX and 5-FU combinations, when compared with TMQ or TMQ and 5-FU, suggests that polyglutamylation of MTX may contribute to the cytotoxicity of this antifolate to breast cancer cells. Hence, these studies suggest that a priming and nontoxic dose of 5-FU before high-dose MTX sustains MTX cytotoxicity in breast cancer and protects against MTX toxicity to bone marrow progenitor cells.

Antimetabolites, Antineoplastic↗
PubMed1999

Molecular modelling of trimethoprim complexes of human wild-type and mutant dihydrofolate reductases: identification of two subsets of binding residues in the antifolate binding site.

Computer-assisted molecular modelling was used to generate structures for the trimethoprim (TMP):NADPH:dihydrofolate reductase (DHFR) ternary complexes for human wild-type DHFR and for five DHFR mutants (L22R, L22F, F31S, F31W and Q35P). The mutants correspond to DHFR proteins that have been isolated from tissues exposed to chronic or high dose methotrexate (MTX) and show decreased sensitivity to antifolate inhibition. Analysis of the TMP:DHFR interactions suggest the presence of two subsets of TMP binding residues in the DHFR antifolate binding site. One subset of these residues (GLU30, PHE34, ILE60 and VAL115) are common to each DHFR complex studied and are referred to as core residues. The other TMP binding residues vary among the DHFR complexes studied and are referred to as noncore residues. The core residues exhibit a greater number of TMP contacts/residue and form more stable TMP interactions than noncore residues. Additionally, the core and noncore residues make contact with different regions of the TMP structure. Information presented here provides additional insight into the design of new agents for the improved inhibition of wild-type DHFR and the simultaneous inhibition of both wild-type and mutant DHFR molecules.

Binding Sites↗
PubMed1999

Photorhabdus toxins: novel biological insecticides.

Following concerns over the potential for insect resistance to insecticidal Bacillus thuringiensis toxins expressed in transgenic plants, there has been recent interest in novel biological insecticides. Over the past year there has been considerable progress in the cloning of several alternative toxin genes from the bacteria Photorhabdus luminescens and Xenorhabdus nematophilus. These genes encode large insecticidal toxin complexes with little homology to other known toxins.

Amino Acid Sequence↗
PubMed1999

The Physical Activity for Total Health (PATH) Study: rationale and design.

PURPOSE: Physical activity has been associated with a decreased risk for breast cancer. Mechanisms for this association may involve hormonal pathways. The Physical Activity for Total Health study is testing the effect of a 1-yr moderate intensity physical activity intervention on the endogenous sex hormone profile of postmenopausal women in a randomized controlled study. METHODS: Women (N = 168) who are aged 55-75 yr, not using sex hormones, sedentary, nonsmokers, have no endocrine-related disease or cancer, and with body mass index of 25.0 or greater, are eligible. Women are recruited through mass mailings and media advertising and are randomized to either a 1-yr moderate intensity aerobic and strength training exercise program (monitored group exercise sessions plus home exercise) or a control program (stretching classes). RESULTS: Serum hormones to be assayed at baseline and at the end of the study include: total estrone, total estradiol, free estradiol, percent bioavailable estradiol, estrone sulfate, sex hormone binding globulin, albumin, testosterone, free testosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, insulin, glucose, and triglycerides. Other outcome measures include: the ratio of urinary 2-hydroxyestrone: 16alpha-hydroxyestrone (an estrogen metabolite ratio that may be associated with risk for breast cancer), weight, body mass index, total fat mass, and body fat distribution (waist:hip circumference ratio, DEXA scan, and abdominal fat measured by computed tomography). CONCLUSION: This study is the first to examine the effect of change in physical activity level on sex hormones in postmenopausal women. It will provide insight into possible mechanisms through which physical activity might be associated with reduced risk of breast cancer.

Aged↗
PubMed1999

Exercise clinical trials in cancer prevention research: a call to action.

The experimental study design can yield valuable information in measuring the association between physical activity and occurrence of cancers. Randomized clinical exercise trials can provide insight into the avenues through which physical activity might affect cancer development and can provide experience with diffusing an exercise intervention into certain populations. This report describes the potential utility of the randomized clinical trial design in providing answers about bias, mechanisms, behavior change, and dose-response in defining the causal pathway between physical activity and cancer. The challenges and limitations of exercise clinical trial are discussed. The research experience in cardiovascular disease and exercise is used as a model for developing a research agenda to explore the potential role of physical activity as a cancer-prevention modality. We recommend that a series of small clinical trials of exercise interventions be conducted to measure exercise change effects on biomarkers for cancer risk, to learn about exercise behavior change in individuals at risk for cancer, and to serve as feasibility studies for larger randomized controlled trials of cancer and precursor end points and for community intervention studies.

Attitude to Health↗
PubMed1999

Participation in breast cancer risk counseling among women with a family history.

Recent scientific breakthroughs in the genetics of breast cancer may have had effects on women's perceptions of risk and subsequent worry about breast cancer. Here, we present the rates of interest in counseling among women identified from diverse sources, their levels of cancer worry and perceived risk, and predictors of their agreement to participate in breast cancer risk counseling. Women were identified through breast cancer cases and through media offers. They completed a telephone survey and were ultimately either entered or not entered into a counseling trial. Overall, almost half (46%) of cases who were approached responded to the contact letter asking for information about potentially interested relatives. A total of 588 women responded to the brief media solicitations over a 15-week period. Participants recruited from media contacts reported slightly but significantly higher levels of worry about getting cancer, compared to case-recruited participants. Cancer worry negatively and significantly predicted entry into the counseling project. The results presented here may have implications for recruiting women in the general population with a family history of breast cancer for counseling about their risk for the disease.

Adolescent↗
PubMed1998

Insecticidal toxins from the bacterium Photorhabdus luminescens.

Transgenic plants expressing Bacillus thuringiensis (Bt) toxins are currently being deployed for insect control. In response to concerns about Bt resistance, we investigated a toxin secreted by a different bacterium Photorhabdus luminescens, which lives in the gut of entomophagous nematodes. In insects infected by the nematode, the bacteria are released into the insect hemocoel; the insect dies and the nematodes and bacteria replicate in the cadaver. The toxin consists of a series of four native complexes encoded by toxin complex loci tca, tcb, tcc, and tcd. Both tca and tcd encode complexes with high oral toxicity to Manduca sexta and therefore they represent potential alternatives to Bt for transgenic deployment.

Amino Acid Sequence↗
PubMed1998

Recruitment strategies in the women's health trial: feasibility study in minority populations. WHT:FSMP Investigators Group. Women's Health Trial:Feasibility Study in Minority Populations.

The Women's Health Trial:Feasibility Study in Minority Populations (WHT:FSMP) examined the feasibility of recruiting postmenopausal women from a broad range of racial and socioeconomic backgrounds into a primary prevention trial requiring marked reductions in dietary fat. Postmenopausal women aged 50-79 yr who had no history of cardiovascular disease or cancer and who consumed 36% or more total energy from fat qualified to participate. We randomized the women into dietary intervention (60%) or control (40%) groups; we aimed to randomize 750 women in 18 months in each of the three clinical centers. All centers achieved goals for randomization based on ethnicity, and two centers exceeded overall recruitment goals. The greatest source of randomized participants was mass mailing, followed by items in the media, referrals, and community outreach. Recruitment yields were generally similar for the ethnic groups but lower for less-educated participants. The experience of WHT:FSMP indicates that postmenopausal women from the African-American, Hispanic, and non-Hispanic white communities can be recruited into dietary intervention studies for the prevention of disease.

Black or African American↗
PubMed1998

The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia.

Evidence from animal, human cross-sectional, case-control, and prospective studies indicate that hormone replacement therapy (HRT) is a promising treatment to delay the onset of symptoms of dementia. The Women's Health Initiative Memory Study (WHIMS) is the first double-masked, randomized, placebo-controlled, long-term clinical trial designed to test the hypothesis that HRT reduces the incidence of all-cause dementia in women aged 65 and older. WHIMS, an ancillary study to the Women's Health Initiative (WHI) funded by the National Institutes of Health, will recruit a subgroup of women aged 65 and older from among those enrolling in the HRT trial of the WHI. The WHI clinical centers and 10 affiliated satellites plan to enroll approximately 8300 women into WHIMS over a 2-year period. Participants will be followed annually for 6 years, receiving cognitive assessments via the Modified Mini-Mental State (3MS) Examination. Women who screen positively for cognitive impairment on the basis of an educational and age-adjusted 3MS cutpoint proceed to more extensive neuropsychological testing and neurologic evaluation. Each woman suspected to have dementia then undergoes a series of laboratory tests that confirm the clinical diagnosis and classify the type of dementia. WHIMS is designed to provide more than 80% statistical power to detect a 40% reduction in the rate of all-cause dementia, an effect that could have profound public health implications for older women's health and functioning.

Aged↗
PubMed1998

A novel insecticidal toxin from photorhabdus luminescens, toxin complex a (Tca), and its histopathological effects on the midgut of manduca sexta

Photorhabdus luminescens is a bacterium which is mutualistic with entomophagous nematodes and which secretes high-molecular-weight toxin complexes following its release into the insect hemocoel upon nematode invasion. Thus, unlike other protein toxins from Bacillus thuringiensis (delta-endotoxins and Vip's), P. luminescens toxin (Pht) normally acts from within the insect hemocoel. Unexpectedly, therefore, the toxin complex has both oral and injectable activities against a wide range of insects. We have recently fractionated the protein toxin and shown it to consist of several native complexes, the most abundant of which we have termed Toxin complex a (Tca). This complex is highly active against the lepidopteran Manduca sexta. In view of the difference in the normal mode of delivery of P. luminescens toxin and the apparent communality in the histopathological effects of other gut-active toxins from B. thuringiensis, as well as cholesterol oxidase, we were interested in investigating the effects of purified Tca protein on larvae of M. sexta. Here we report that the histopathology of the M. sexta midgut is similar to that for other novel midgut-active toxins. Following oral ingestion of Tca by M. sexta, we observed an acceleration in the blebbing of the midgut epithelium into the gut lumen and eventual lysis of the epithelium. The midgut shows a similar histopathology following injection of Tca into the insect hemocoel. These results not only show that Tca is a highly active oral insecticide but also confirm the similar histopathologies of a range of very different gut-active toxins, despite presumed differences in modes of action and/or delivery. The implications for the mode of action of Tca are discussed.

Journal Article↗
PubMed1998

A health priorities model: application to mammography screening.

This study describes and empirically tests a health priorities model. This model predicts underuse of regular mammography screening among adult women within the larger health context in which such decisions are made. The model incorporates women's comparative illness threats, comparative importance of health behaviors, and demographic variables. A telephone survey was conducted with a sample of women (N = 887) older than 50, in 40 rural communities in the state of Washington. Logistic regression analyses showed that women who perceived themselves at low risk for getting breast cancer and/or who perceived another disease (i.e. heart attack) as an equal or greater threat than breast cancer were less likely to be regular screeners of mammography. In addition, women who perceived other health behaviors as more important than regular mammography screening were less likely to be regular screeners than those women who perceived regular mammography screening as more important. Current or anticipated health problems were not related to screening behavior. The results are discussed in light of the practical, theoretical, and empirical implications.

Aged↗
PubMed1997

Comparing patient satisfaction, outcomes and costs between cataract day surgery and inpatient surgery for elderly people.

The study reported in this paper examined the characteristics of elderly people undergoing cataract surgery and compared patient perspectives and satisfaction, outcome, costs, reported health problems and social circumstances of day surgery patients and hospital inpatients. The study sample was drawn from the client database of a health insurance fund and covered 291 people aged 60 years or more who had recently undergone cataract surgery. Overall, both day surgery patients and inpatients indicated a high level of satisfaction with their eye surgery (about 80 per cent for both groups). The majority of patients from both groups reported an improved level of vision, with vision outcome in the day surgery group being as good as in the inpatient group. Overall, inpatient treatment was more costly and involved higher out of pocket expenses. The study results indicate a potential to increase the number of patients undergoing cataract surgery as a day patient procedure. Pre-operative preparation contributed to patient satisfaction and the availability of family and/or social support was an important factor influencing day surgery admission. Whilst patients reporting health problems were less inclined to have cataract surgery than were day patients, this only accounted for one-fifth of the total inpatient group. Developing systematic and appropriate case selection criteria and effective case management will contribute to more efficient use of hospital resources, an increased use of day surgery facilities, and hence a more cost-effective overall cataract surgery service for elderly people.

Aged↗
PubMed1996

The Women's Health Trial Feasibility Study in Minority Populations: design and baseline descriptions.

The Women's Health Trial: Feasibility Study in Minority Populations (WHT:FSMP), a randomized trial of 2208 women, was conducted to investigate three questions. First, can women from minority and low-socioeconomic-status populations be recruited in numbers sufficient to evaluate a dietary intervention designed to lower fat intake. Second, the efficacy of a low fat, increased fruit/vegetable/ grain product intervention for reducing fat consumption. Third, will participation in the intervention lower plasma cholesterol and estradiol levels relative to the controls. The baseline results showed that an adequate number of minority and low SES women could be recruited to test the study hypotheses. A diverse study population of postmenopausal women consuming a high fat diet was recruited: 28% of participants were Black, 16% were Hispanic, 11% had less than a high school level of education, and 15.5% had household incomes of < $15,000.

Aged↗
PubMed1996

Cytometric analysis and maturation characteristics of reticulocytes from myelodysplastic patients.

Myelodysplasia is characterized by a hypoproliferative anaemia with ineffective intramedullary erythropoiesis. We have used the novel technology of the Bayer H3 analyser to characterize reticulocytes (RNA containing red cells) from 32 MDS patients and 10 elderly normal subjects. In comparison with reticulocytes from normal subjects, those from MDS patients were larger with a lower haemoglobin concentration. Reticulocytes from sideroblastic patients had a lower haemoglobin content and concentration than for refractory anaemia patients but no other differences between FAB subtypes were found. H3 reticulocyte RNA content parameters correlated poorly with those derived by the Sysmex R-1000, particularly in the MDS group. On reticulocyte maturation to red cells MDS patients concentrated haemoglobin more than normal subjects and this was most evident in the sideroblastic group. Platelet depletion of whole blood suggested that large platelets in the sideroblastic group may have partly contributed to this observation. Prospective evaluation of changes towards normal reticulocyte cytometric parameters may assist in assessment of early erythroid response to therapy in MDS patients.

Adult↗