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Biomedical subjects

R Warren

Publications and source records attributed to R Warren.

At least 73 records · Page 4Linked to original sources
PubMed2000

Efflux and target mutations as quinolone resistance mechanisms in clinical isolates of Streptococcus pneumoniae.

The aim of this study was to characterize quinolone resistance mechanisms in strains of Streptococcus pneumoniae with increased MICs of ofloxacin. These strains were also tested for their susceptibility to a battery of quinolone antimicrobial agents, including gemifloxacin. Of the S. pneumoniae isolates used, 27 were susceptible to ofloxacin, 18 intermediate and 48 resistant (ofloxacin MIC <4, 4 and >4 mg/L, respectively). In general, the ofloxacin-susceptible strains had no amino acid substitutions in GyrA, GyrB, ParC or ParE. Moderate increases in MIC were associated with substitutions in the quinolone resistance-determining region (QRDR) of ParC, while the highest MICs were found for strains that also had substitutions in the QRDR of GyrA. The most common substitutions were Ser79-->Phe in ParC and Ser81-->Phe in GyrA. Other substitutions were identified within the QRDR of ParC and outside the QRDR of ParC and ParE; these did not appear to affect susceptibility. The effects of antimicrobial efflux pumps were studied by determining MICs of a range of quinolones in the presence and absence of reserpine, an inhibitor of Gram-positive efflux pumps. Our results indicated that high-level resistance, caused entirely by efflux, was seen in a minority of ofloxacin-resistant S. pneumoniae strains. Testing the susceptibility of quinolone-resistant strains to gemifloxacin, ciprofloxacin, norfloxacin, ofloxacin and trovafloxacin revealed that gemifloxacin was least affected by this large variety of resistance mechanisms and was the only quinolone with MICs of < or =0.5 mg/L for all strains in this study. These results suggest that gemifloxacin is highly potent against S. pneumoniae and may also be effective against strains resistant to other quinolones.

Anti-Infective Agents↗
PubMed2000

Improving the detection of cancer in the screening of mammograms.

OBJECTIVE: Examination of figures from screening at several different centres, and from the incidence of interval cancers in those programmes, suggests that a single radiologist reading by him/herself would miss 16 to 31% of cancers detectable in the mammograms. This study investigates how the accuracy of breast cancer screening could be improved. METHOD: Draw a comparison between screening for breast cancer and other inspection tasks that have been studied in the experimental psychological laboratory to suggest two low cost fixes that might improve the accuracy of breast cancer screening. RECOMMENDATIONS: (1) Radiologists should not work for more than half an hour at a time; (2) two radiologists double reading should inspect the same series of mammograms in inverse order; (3) there should be a clerical check to see whether the efficiency of detection decreases with time on task; and (4) a more sophisticated engineering of the screening procedure might be accomplished by assembling a library of mammograms for which the correct diagnosis is known. If these library mammograms were mixed randomly with those to be inspected in some suitable ratio, it would then be possible to provide the radiologist with immediate feedback on the accuracy of (some of) his/her diagnoses. From experimental studies of inspection tasks this should improve diagnostic accuracy. These recommendations, of course, require evaluation in field trials.

Breast Neoplasms↗
PubMed2000

A functional proteomics screen of proteases in colorectal carcinoma.

BACKGROUND: Proteases facilitate several steps in cancer progression. To identify proteases most suitable for drug targeting, actual enzyme activity and not messenger RNA levels or immunoassay of protein is the ideal assay readout. MATERIALS AND METHODS: An automated microtiter plate assay format was modified to allow detection of all four major classes of proteases in tissue samples. Fifteen sets of colorectal carcinoma biopsies representing primary tumor, adjacent normal colon, and liver metastases were screened for protease activity. RESULTS: The major proteases detected were matrix metalloproteases (MMP9, MMP2, and MMP1), cathepsin B, cathepsin D, and the mast cell serine proteases, tryptase and chymase. Matrix metalloproteases were expressed at higher levels in the primary tumor than in adjacent normal tissue. The mast cell proteases, in contrast, were at very high levels in adjacent normal tissue, and not detectable in the metastases. Cathepsin B activity was significantly higher in the primary tumor, and highest in the metastases. The major proteases detected by activity assays were then localized in biopsy sections by immunohistochemistry. Mast cell proteases were abundant in adjacent normal tissue, because of infiltration of the lamina propria by mast cells. Matrix metalloproteases were localized to the tumor cells themselves; whereas, cathepsin B was predominantly expressed by macrophages at the leading edge of invading tumors. Although only low levels of urinary plasminogen activator were detected by direct enzyme assay, immunohistochemistry showed abundant protein within the tumor. CONCLUSIONS: This analysis, surveying all major classes of proteases by assays of activity rather than immunolocalization or in situ hybridization alone, serves to identify proteases whose activity is not completely balanced by endogenous inhibitors and which may be essential for tumor progression. These proteases are logical targets for initial efforts to produce low molecular weight protease inhibitors as potential chemotherapy.

Biopsy↗
PubMed1999

Smoking and high-risk mammographic parenchymal patterns: a case-control study.

STATEMENT OF FINDINGS: Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern. Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to the mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results are still strongly suggestive. The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate that smoking is a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It appears that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.

Breast Neoplasms↗
PubMed1999

Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment.

BACKGROUND: For decades it has been assumed that postprimary tuberculosis is usually caused by reactivation of endogenous infection rather than by a new, exogenous infection. METHODS: We performed DNA fingerprinting with restriction-fragment-length polymorphism analysis on pairs of isolates of Mycobacterium tuberculosis from 16 compliant patients who had a relapse of pulmonary tuberculosis after curative treatment of postprimary tuberculosis. The patients lived in areas of South Africa where tuberculosis is endemic. Medical records were reviewed for clinical data. RESULTS: For 12 of the 16 patients, the restriction-fragment-length polymorphism banding patterns for the isolates obtained after the relapse were different from those for the isolates from the initial tuberculous disease. This finding indicates that reinfection was the cause of the recurrence of tuberculosis after curative treatment. Two patients had reinfections with a multidrug-resistant strain. All 15 patients who were tested for the human immunodeficiency virus were seronegative. CONCLUSIONS: Exogenous reinfection appears to be a major cause of postprimary tuberculosis after a previous cure in an area with a high incidence of this disease. This finding emphasizes the importance of achieving cures and of preventing anyone with infectious tuberculosis from exposing others to the disease.

Adult↗
PubMed1999

A case of discordant related abnormal karyotypes from chorionic villi and amniocytes.

A case of three discordant cell lines in prenatal diagnosis is described, of which two were abnormal related structural abnormalities of chromosome 11. One of the abnormal cell lines was seen in all metaphases examined from direct preparations of chorionic villi, the cultured preparations showing an apparently normal male karyotype; the other abnormal cell line was seen in conjunction with a normal cell line in cultured amniocytes. Prenatal diagnosis offered solely on chorionic villus sampling would have yielded a mistakenly normal result on the basis of established criteria for distinguishing true mosaicism from confined placental mosaicism.

Adult↗
PubMed1999

DNA fingerprinting and molecular epidemiology of tuberculosis: use and interpretation in an epidemic setting.

Tuberculosis (TB) is still a major cause of morbidity and mortality. It is clear that control requires more than simple availability of antibiotics. In order to gain insight into the disease, DNA fingerprinting has been applied to the study of bacterial population structure. This technology has been used to quantitate various components of the disease in a high-incidence community, viz. recent transmission (RT) and reactivation (RA) and to monitor these over time as a tool to quantitate changes in the epidemic. In our high-incidence community, we find unexpectedly high strain diversity, lower than predicted RT, and that reactivation disease dominates. This technology can be used to examine and challenge traditional dogmas. Quantitative measure of RT varies over time, using a two-year sliding window for estimation as a useful period. The results show that the "epidemic" consists of subepidemics characterized by strain families that wax and wane in the community of TB patients. The technology is shown to be a useful and quantitative tool to assess disease status and can therefore be used to monitor intervention strategies and refine and monitor results of new control measures.

DNA Fingerprinting↗
PubMed1999

Cyclic GMP-gated channel and peripherin/rds-rom-1 complex of rod cells.

The cGMP-gated channel and the peripherin/rds-rom-1 complex are two oligomeric membrane proteins that play key roles in the structure and function of photoreceptor outer segments. The channel is localized on the plasma membrane where it controls the flow of Na+ and Ca2+ into the outer segment in response to light-induced changes in cGMP. The rod channel consists of two homologous subunits, designated alpha and beta, which assemble into a heterotetrameric complex. Both subunits contain a core structural unit consisting of six transmembrane segments, a pore region and a cGMP binding domain. The alpha subunit is the dominant functional subunit since it forms a functional channel by itself. The beta subunit does not assemble into a functional channel by itself, but modulates the activity of the channel. The peripherin/rds-rom-1 complex is localized along the rim region of disk membranes where it plays a crucial role in disk morphogenesis. This complex consists of two peripherin/rds and two rom-1 subunits that interact non-covalently to form a heterotetramer. Peripherin/rds is the dominant subunit since, in the absence of rom-1, it self-assembles into a homotetramer that effectively supports outer segment disk formation and structure. Rom-1 on its own does not initiate outer segment formation. Instead, it plays a minor role in fine tuning disk structure. Recently, peripherin/rds-containing tetramers have been shown to form disulfide-mediated higher-order oligomers. This novel oligomerization is suggested to play a central role in outer segment disk formation.

Cyclic GMP↗
PubMed1999

Transcatheter embolization for the treatment of misperfusion after hepatic artery chemoinfusion pump implantation.

BACKGROUND: The use of surgically implanted chemoinfusion pumps for the treatment of hepatic metastases from colorectal carcinoma can be complicated by intra- or extrahepatic misperfusion. This may result in suboptimal tumor exposure to the chemotherapeutic agent and injury to other gastrointestinal organs. Misperfusion can be managed by selective arterial transcatheter embolization. METHODS: Between 1989 and 1996, 16 patients with liver metastases from colorectal carcinoma and with hepatic artery chemoinfusion pump misperfusion were treated using transcatheter coil embolization. Six female and 10 male patients (age range, 34-84 years; median, 51.5 years) were identified by retrospective review of the records of the Department of Interventional Radiology. After pump placement, abnormal liver perfusion scan or methylene blue endoscopy study results prompted angiography with coil embolization. After embolization, the imaging studies were repeated and patients were monitored in the Oncology Clinic. RESULTS: Eight patients exhibited intrahepatic misperfusion (group 1) and eight extrahepatic misperfusion (group 2). Coil embolization was immediately successful in 100% of patients in group 1, with restoration of normal hepatic perfusion, and in 75% in group 2. There were no immediate procedure-related complications. Follow-up periods ranged from 1 to 23 months (median, 13.5 months). Embolization was unsuccessful for two patients (in group 2), who tolerated a modified chemotherapeutic regimen, with follow-up periods of 18.5 and 22 months. CONCLUSIONS: Transcatheter coil embolization is the therapy of choice for the management of hepatic artery chemoinfusion pump misperfusion. It is rapid, effective, and well tolerated by patients and obviates the need for additional surgical intervention.

Adult↗
PubMed1999

High-risk mammographic parenchymal patterns and anthropometric measures: a case-control study.

Mammographic parenchymal patterns are related to breast cancer risk and are also affected by anthropometric measure. We carried out a case-control study comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern and 200 controls with low-risk (N1 and P1) patterns in order to investigate the effect of body size and shape and breast size on mammographic patterns. Women in the highest quartile of body mass index (BMI) distribution were significantly less likely to have a high-risk pattern (odds ratio (OR) = 0.21, 95% confidence interval (CI) 0.08-0.52, P-value for trend = 0.001) compared to those in the lowest quartile. Relative to women with a waist to hip ratio (WHR) of less than 0.75, the OR of having a high-risk pattern in women with a WHR greater than 0.80 was 0.30 (95% CI 0.14-0.63). Breast size as measured by cup size was significantly and negatively related to high-risk pattern. Our study indicates that both BMI and WHR are negatively associated with high-risk patterns. However, both phenomena are associated with increased risk of breast cancer in postmenopausal women. This negative confounding of two positive risk factors means that the effect of parenchymal patterns on risk will tend to be underestimated when not adjusted for BMI and WHR and vice versa. Thus we may have underestimated the importance of BMI and mammographic parenchymal patterns in the past. Further studies are needed to determine a measure of parenchymal density that is independent of anthropometric measures and breast size.

Aged↗
PubMed1999

Detection of mutations in drug resistance genes of Mycobacterium tuberculosis by a dot-blot hybridization strategy.

SETTING: Mycobacterium tuberculosis isolates from patients in communities endemic for tuberculosis in South Africa. OBJECTIVE: To develop a reliable PCR-based dot-blot hybridization strategy to detect mutations conferring drug resistance. DESIGN: Different loci in six genes associated with drug resistance to isoniazid, rifampacin, streptomycin and ethambutol were selected to develop the PCR-based dot-blot hybridization strategy. RESULTS: Primers and probes to detect mutations at codons 315, 463 (katG) 269 (kasA), 531, 526 (rpoB) 43 (rpsL), 513 (rrs) and 306 (embB) were designed and used to develop a PCR-based dot-blot hybridization strategy. The dot-blot hybridization strategy with wild-type probes can efficiently be used to detect drug resistant mutations since these do not hybridize to mutant loci. Stripped blots and mutant probes can be used to identify the precise mutation. The embB gene (ethambutol resistance) was used to show how the dot-blot strategy can assist with the prediction of drug resistance more accurately. The method is rapid, reproducible, not technically demanding and samples can be done in batches. Additional loci can easily be incorporated. CONCLUSIONS: A PCR-based dot-blot hybridization strategy is described which can accurately identify drug resistant strains and the method is useful for patients at risk and in areas endemic for tuberculosis.

Antitubercular Agents↗
PubMed1999

Cross-cultural research: trying to do it better. 2. Enhancing data quality.

OBJECTIVE: To describe the dilemmas for cross-cultural research in translating study instruments and implementing quality assurance methods, drawing on strategies utilised in the Mothers in a New Country (MINC) Study. METHOD: To translation of study instruments in the MINC Study included: forward and back translations, a bilingual group review process, consultation with bilingual content experts, piloting of different versions of translations, a process for exploring unresolved difficulties and caution in interpreting unusual study findings. Interview quality was assessed by: 1. An ongoing review of interviewer-prepared English coding schedules to ensure completeness of data and identify problems with interview administration. 2. Analysis of fully translated transcripts of six randomly selected early interviews to assess the accuracy and consistency with which questions were asked. 3. A comparison of data sources for 45 randomly selected interviews (original language interview schedules, English coding schedules and translated interview transcripts) to determine the rate and nature of discrepancies. RESULTS: Translation strategies that went beyond simple forward and back translations achieved more reliable and appropriate translations. The complexity of language and cultural differences sometimes still meant less than satisfactory results. Interview tapes played an important quality assurance role, enabling feedback to the interviewers and providing a basis of comparison for identification of data discrepancies. IMPLICATIONS: Ensuring good data quality in cross-cultural research is both critically important and difficult. Open discussion of the problems and concerted efforts to deal with them would benefit future research.

Attitude to Health↗
PubMed1999

Impact of social interactions in the community on the transmission of tuberculosis in a high incidence area.

BACKGROUND: Tuberculosis (TB) is transmitted by close contact with an infectious person. It is assumed that close contact occurs amongst household members and that contact outside the house is "causal" and does not play a major role in the transmission of TB. METHODS: This study was conducted in an impoverished area with a high incidence of TB and a low HIV seropositive prevalence. Thirty three households with 84 TB patients were identified between February 1993 and April 1996 and the transmission of TB was studied by combining Mycobacterium tuberculosis fingerprinting with in depth sociological interviews. RESULTS: Forty two strain genotypes were identified in the 84 patients. In 15 households all the patients had identical strains, in nine households all the patients had different strains, and in nine households some patients had identical strains and one had a different strain. In 26 houses at least one patient had a strain which formed part of a larger community cluster and in 12 of these households the patient(s) had contact with a community member who had the identical strain. In 58% of the cases the contact took place while drinking in social groups. CONCLUSION: In high incidence areas contact outside the household may be important for the transmission of TB. This contact often takes place during recreation which, in the case of this study of impoverished people, consisted of drinking in social groups. Social interaction patterns should be studied and understood for effective implementation of control strategies.

Disease Transmission, Infectious↗
PubMed1999

Mammographic patterns as a predictive biomarker of breast cancer risk: effect of tamoxifen.

Mammographic breast density has been shown to be associated with up to a 4- to 6-fold increase in risk of breast cancer, whereas tamoxifen therapy increases disease-free survival and reduces mortality. We have therefore investigated whether these effects are related. To determine the effects of tamoxifen on mammographic density, mammograms from 94 women who had received tamoxifen for breast cancer and 188 women (without breast cancer) who had not received tamoxifen were visually classified according to the criteria of Wolfe. Two controls were age-matched to each case. All of the women were postmenopausal (ages, 50-64 years), neither group was taking hormone replacement therapy, and none of the cases had received chemotherapy. There were significant differences in breast density between cases and controls at the initial mammogram (P = 0.0001) but no significant differences at the follow-up mammogram (P = 0.51). A significant change to a more lucent pattern had occurred among the case group (P = 0.0001). The odds ratio for cancer that was associated with the more dense (P2 and DY) patterns with respect to the more lucent (N1 and P1) patterns was 3.6 (95% confidence interval, 2.11-6.18) at the initial mammogram. This was significantly reduced to 1.5 (95% confidence interval, 1.32-1.70) after treatment with tamoxifen (P = 0.019; chi2 = 5.52). The substantial reduction in breast density with tamoxifen provides evidence that tamoxifen has the capacity to favorably alter postmenopausal breast density toward a more lucent pattern, which is associated with reduced risk of breast cancer. Mammographic pattern is, thus, a potential biomarker of breast cancer risk.

Antineoplastic Agents, Hormonal↗
PubMed1998

Support, sensitivity, satisfaction: Filipino, Turkish and Vietnamese women's experiences of postnatal hospital stay.

OBJECTIVE: To assess Filipino, Turkish and Vietnamese women's views about their care during the postnatal hospital stay. DESIGN: Interviews were conducted with recent mothers in the language of the women's choice, 6-9 months after birth, by three bilingual interviewers. PARTICIPANTS: Three hundred and eighteen women born in the Philippines (107), Turkey (107) and Vietnam (104) who had migrated to Australia. SETTING: Women were recruited from the postnatal wards of three maternity teaching hospitals in Melbourne, Australia, and interviewed at home. FINDINGS: Overall satisfaction with care was low, and one in three women left hospital feeling that they required more support and assistance with both baby care and their own personal needs. The method of baby feeding varied between the groups, with women giving some insight into the reason for their choice. A significant minority wanted more help with feeding, irrespective of the method. The need for rest was a recurrent theme, with women stating that staff's attitudes to individual preferences, coupled with lack of assistance, made this difficult. The majority of comments women made regarding their postnatal stay focused on the attitude and behaviour of staff and about routine aspects of care. Issues related to culture and cultural practices were not of primary concern to women. CONCLUSION: Maternity services need to consider ways in which care can focus on the individual needs and preferences of women.

Adult↗