Cervical screening for women with learning disability. Numbers screened can be optimised by using a focused initiative.
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Female↗
Biomedical subjects
E Ward
Publications and source records attributed to E Ward.
HPV 16 antibody prevalence in Jamaica and the United States reflects differences in cervical cancer rates.
Human papillomavirus (HPV) is widely accepted as the primary etiologic agent in the development of cervical cancer. DNA of a particular HPV type, HPV 16, is found in about half of tumors tested. Inconsistent with this causal relationship, however, population-based studies of HPV DNA prevalence have often failed to find high rates of anogenital HPV infection in countries with high cervical cancer rates. To examine this issue, we used serology to compare HPV 16 exposure in healthy volunteer blood donors in the United States (n = 278) and similar subjects from a country with 3-fold higher cervical cancer rates, Jamaica (n = 257). Jamaican sexually transmitted disease (STD) patients (n = 831) were also studied to examine in detail the relation of HPV 16 antibodies with sexual history. Serology was conducted using an ELISA employing HPV 16 virus-like particles (VLPs). Age-adjusted seroprevalence rates were greatest among male (29%) and female (42%) STD patients, intermediate in male (19%) and female (24%) Jamaican blood donors and lowest among male (3%) and female (12%) U.S. blood donors. The higher seroprevalence in women was significant, and prevalence tended to increase with age. In multivariate logistic regression, controlling for age and gender, Jamaican blood donors were 4.2-fold (95% CI 2.4-7.2) and STD patients 8.1-fold (95% CI 5.0-13.2) more likely to have HPV 16 VLP antibodies than U.S. blood donors. Among STD patients, HPV 16 antibodies were associated with lifetime number of sex partners and years of sexual activity, as well as other factors. Our data suggest that HPV 16 VLP antibodies are strongly associated with sexual behavior. Moreover, exposure to HPV 16 appears to be much greater in Jamaica than in the United States, consistent with the high rate of cervical cancer in Jamaica.
Adolescent↗
Target-based discovery of crop protection chemicals.
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Agrochemicals↗
Inhibition of protoporphyrinogen oxidase expression in Arabidopsis causes a lesion-mimic phenotype that induces systemic acquired resistance.
We have used an antisense expression technology in Arabidopsis based on the yeast GAL4/UAS transactivation system (Guyer et al., Genetics, 1998; 149:633-639) to reduce levels of protoporphyrinogen IX oxidase (PPO), the last common enzyme of the biosynthesis of the haem group and chlorophyll. Plants expressing the antisense PPO gene presented growth alterations and their leaves showed necrotic lesions that appeared similar to lesions characteristic of the pathogen-induced hypersensitive reaction, and seen in the so-called lesion-mimic mutants. Plants expressing the antisense gene also had high endogenous salicylic acid levels, constitutive expression of the PR-1 gene, and were resistant to Peronospora parasitica, consistent with the activation of systemic acquired resistance (SAR). Treatment of wild-type plants with sublethal concentrations of herbicides that inhibit PPO also induced defence responses that conferred enhanced tolerance to P. parasitica. This effect was not observed in NahG and nim1 plants, which are compromised in their ability to activate SAR. These results demonstrate that genetic or chemical disruption of a metabolic pathway can lead to the induction of a set of defence responses including activation of SAR.
Arabidopsis↗
zfh-1, the Drosophila homologue of ZEB, is a transcriptional repressor that regulates somatic myogenesis.
zfh-1 is a member of the zfh family of proteins, which all contain zinc finger and homeodomains. The roles and mechanisms of action of most family members are still unclear. However, we have shown previously that another member of the family, the vertebrate ZEB protein, is a transcriptional repressor that binds E box sequences and inhibits myotube formation in cell culture assays. zfh-1 is downregulated in Drosophila embryos prior to myogenesis. Embryos with zfh-1 loss-of-function mutation show alterations in the number and position of embryonic somatic muscles, suggesting that zfh-1 could have a regulatory role in myogenesis. However, nothing is known about the nature or mechanism of action of zfh-1. Here, we demonstrate that zfh-1 is a transcription factor that binds E box sequences and acts as an active transcriptional repressor. When zfh-1 expression was maintained in the embryo beyond its normal temporal pattern of downregulation, the differentiation of somatic but not visceral muscle was blocked. One potential target of zfh-1 in somatic myogenesis could be the myogenic factor mef2. mef2 is known to be regulated by the transcription factor twist, and we show here that zfh-1 binds to sites in the mef2 upstream regulatory region and inhibits twist transcriptional activation. Even though there is little sequence similarity in the repressor domains of ZEB and zfh-1, we present evidence that zfh-1 is the functional homologue of ZEB and that the role of these proteins in myogenesis is conserved from Drosophila to mammals.
Animals↗
Conducting randomized trials in general practice: methodological and practical issues.
The evaluation of the outcome of health services technologies is a requirement for their efficient provision in clinical practice. The most reliable evidence for treatment efficacy comes from randomized trials. Randomized trials in general practice pose particular methodological and practical difficulties. In this paper, we discuss how best to plan and manage a clinical trial in this setting. We base our discussion on our experience of conducting randomized trials to evaluate the effectiveness of brief psychotherapy in general practice.
Ethics, Medical↗
Genotoxicity in workers exposed to methyl bromide.
To address the genotoxicity of in vivo methyl bromide (CAS 74-83-9) exposure in humans, we collected blood and oropharyngeal cells as part of a cross-sectional morbidity study of methyl bromide-exposed fumigation workers and their referents. Micronuclei were measured in lymphocytes and oropharyngeal cells, and hypoxanthine-guanine phosphoribosyl transferase gene (hprt) mutations were measured in lymphocytes. A total of 32 workers and 28 referents provided specimens. Among current non-smokers, mean hprt variant frequencies (Vfs) were found to be elevated among workers compared to referents (geometric mean: workers=4.49x10(-6), referents=2.96x10-(6); two-sided p=0.22); this difference was more pronounced among workers with 4 h or more of recent methyl bromide exposure compared to referents (geometric mean: workers=6.56x10(-6), referents=2.96x10(-6); two-sided p=0.06). Mean oropharyngeal cell micronuclei were higher among workers compared to referents (mean: workers=2.00, referents=1.31; two-sided p=0.08); the results were similar when workers with 4 h or more of recent methyl bromide exposure were compared to referents (mean: workers=2.07, referents=1.31; two-sided p=0.13). No consistent differences between workers and referents were observed for frequencies of kinetochore-negative lymphocyte micronuclei, or kinetochore-positive lymphocyte micronuclei. The study was limited by a sample size sufficient only for detecting relatively large differences, absence of a reliable method to measure the intensity of workplace methyl bromide exposures, and relatively infrequent methyl bromide exposure (e.g., the median length of exposure to methyl bromide during the 2 weeks preceding the survey was 4 h). In conclusion, our findings provide some evidence that methyl bromide exposure may be associated with genotoxic effects in lymphocytes and oropharyngeal cells. Further study on the genotoxicity of methyl bromide exposure in humans is warranted.
Adult↗
Cancer risks among workers exposed to metalworking fluids: a systematic review.
Metalworking fluids (MWFs) are commonly used in a variety of industrial machining and grinding operations. The National Institute for Occupational Safety and Health (NIOSH) estimates that more that one million workers are exposed to MWFs. NIOSH conducted a comprehensive and systematic review of the epidemiologic studies that examined the association between MWF exposure and cancer. Substantial evidence was found for an increased risk of cancer at several sites (larynx, rectum, pancreas, skin, scrotum, and bladder) associated with at least some MWFs used prior to the mid-1970s. This paper provides the evidence pertaining to cancer at these sites. Cancer at those sites found to have more limited or less consistent evidence for an association with MWF (stomach, esophagus, lung, prostate, brain, colon, and hematopoietic system) will not be discussed in this paper but are discussed in the recent NIOSH Criteria for a Recommended Standard-Occupational Exposure to MWFs. Because the changes in MWF composition that have occurred over the last several decades may not be sufficient to eliminate the cancer risks associated with MWF exposure, reductions in airborne MWF exposures are recommended.
Air Pollutants, Occupational↗
Cytochrome P450 superfamily in Arabidopsis thaliana: isolation of cDNAs, differential expression, and RFLP mapping of multiple cytochromes P450.
We have isolated multiple cDNAs encoding cytochromes P450 (P450s) from Arabidopsis thaliana employing a PCR strategy. Degenerate oligonucleotide primers were designed from amino acid sequences conserved between two plant P450s, CYP71A1 and CYP73A2, including the heme-binding site and the proline-rich motif found in the N-terminal region, and 11 putative P450 fragments were amplified from first-strand cDNA from 7-day-old Arabidopsis as a template. With these PCR fragments as hybridization probes, 13 full-length and 3 partial cDNAs encoding different P450s have been isolated from an Arabidopsis cDNA library. These P450s have been assigned to either one of the established subfamilies: CYP71B, CYP73A, and CYP83A; or novel subfamilies: CYP76C, CYP83B, and CYP91A. The primary protein structures predicted from the cDNA sequences revealed that the regions around both the heme-binding site and the proline-rich motif were highly conserved among all these P450s. The N-terminal structures of the predicted P450 proteins suggested that these Arabidopsis P450s were located at the endoplasmic reticulum membrane. The loci of four P450 genes were determined by RFLP mapping. One of the clones, CYP71B2, was located at a position very close to the ga4 and gai mutations. RNA blot analysis showed expression patterns unique to each of the P450s in terms of tissue specificity and responsiveness to wounding and light/dark cycle, implicating involvement of these P450s in diverse metabolic processes.
Amino Acid Sequence↗
Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models.
ZD1694 (Tomudex, raltitrexed) is a specific quinazoline antifolate thymidylate synthase inhibitor that relies on polyglutamation for high potency. Antibodies to ZD1694 have been used to establish a sensitive radioimmunoassay as an alternative to high-performance liquid chromatography (HPLC). The radioimmunoassay is reproducible, accurate and provides a means of determining low levels of ZD1694 in plasma (< 1 nM). By virtue of the high cross-reactivity of the antibodies with polyglutamated forms of ZD1694, it is also possible to measure the total concentration of drug in tissues. Results obtained in L1210 mouse leukaemia cells and in mouse tissues were similar to those previously determined using radiolabelled drug. Pharmacokinetic studies in mice have confirmed that the compound is rapidly eliminated from the plasma and that there is a prolonged terminal elimination phase. ZD1694 was measured in plasma (0.56 ng ml(-1); 1.2 pmol ml(-1)) up to 7 days after a single i.p. dose of 100 mg kg(-1) ZD1694. Liver, kidney and gut epithelium had a substantially higher level of ZD1694 immunoreactivity than plasma. For example, 24 h after a single i.p. dose at 1, 10 and 100 mg kg(-1), total drug levels in the liver were 480, 325 and 152 times higher than plasma levels respectively. In kidney and gut epithelium, total drug levels at these doses were approximately 55 and 34 times those of plasma. The high tissue to plasma ratios were maintained for at least 7 days after administration. Similarly, high tissue to plasma ratios (> 100) were found in dogs treated with a clinically relevant dose of ZD1694. These were maintained for 4 weeks in liver and kidney tissue (> 100). Total gastrointestinal concentrations of ZD1694 were approximately 10 times higher than plasma 3 days after administration, but levels were near to the limit of detection at 4 weeks. These results are consistent with extensive polyglutamation of ZD1694 within tissues in both mice and dog and provide further support for the infrequent schedule that has been used clinically. Although it has not been possible to measure individual polyglutamated forms of ZD1694, the radioimmunoassay provides a convenient means of assessing total drug levels in tissues and is currently the only method suitable for measuring the extent of drug retention in normal tissue and tumour biopsies obtained from patients treated with ZD1694.
Animals↗
Functional analysis of regulatory sequences controlling PR-1 gene expression in Arabidopsis.
The Arabidopsis PR-1 gene is one of a suite of genes induced co-ordinately during the onset of systemic acquired resistance (SAR), a plant defense pathway triggered by pathogen infection or exogenous application of chemicals such as salicylic acid (SA) and 2,6-dichloroisonicotinic acid (INA). We have characterized cis-acting regulatory elements in the PR-1 promoter involved in INA induction using deletion analysis, linker-scanning mutagenesis, and in vivo footprinting. Compared to promoter fragments of 815 bp or longer (which show greater than 10-fold inducibility after INA treatment), induction of a 698 bp long promoter fragment is reduced by half and promoter fragments of 621 bp or shorter have lost all inducibility. Additionally, two 10-bp linker-scanning mutations centered at 640 bp and 610 bp upstream from the transcription initiation site are each sufficient to abolish chemical inducibility of a GUS reporter fusion. The -640 linker-scanning mutation encompasses a region highly homologous to recognition sites for transcription factors of the basic leucine zipper class, while the -610 linker-scanning mutation contains a sequence similar to a consensus recognition site for the transcription factor NF-kappa B. Furthermore, several inducible in vivo footprints located at or nearby these motifs demonstrate significant and highly reproducible changes in DNA accessibility following SAR induction. This in vivo signature of protein-DNA interactions after INA induction is tightly correlated with the functionally important regions of the promoter identified by mutation analysis.
Arabidopsis↗
Activation of latent transgenes in Arabidopsis using a hybrid transcription factor.
A hybrid transcription factor comprising a fusion of the DNA-binding domain of Saccharomyces cerevisiae GAL4 and the transcription activation domain of maize C1 was expressed in stably transformed Arabidopsis. Additional transgenic lines were created containing test genes controlled by a synthetic promoter consisting of concatemeric copies of the cis-acting site recognized by GAL4 (UASG) fused to a minimal promoter. The GAL4/C1 effector line was crossed to two lines containing a synthetic promoter/GUS fusion. Both histochemical staining and GUS activity assays indicate strong activation of GUS expression was achieved only after crossing. The GAL4/C1 effector line was also crossed to 15 lines containing a synthetic promoter/antisense adenylosuccinate synthetase gene. Severely retarded growth, and in some cases lethality, was observed in 40% of the F1 lines. This system of activation by crossing is generally useful for activating expression of test transgenes.
Arabidopsis↗
Sexually transmitted diseases are common in women attending Jamaican family planning clinics and appropriate detection tools are lacking.
OBJECTIVES: To assess sexually transmitted diseases (STD) among women attending Jamaican family planning clinics and to evaluate decision models as alternatives to STD laboratory diagnosis. METHODS: Women attending two family planning clinics in Kingston were interviewed and tested for syphilis seroreactivity using toluidine red unheated serum test and Treponema pallidum haemagglutination, for gonorrhoea using culture, for chlamydial infection using enzyme linked immunoassay, and for trichomoniasis using culture. Urine was tested with leucocyte esterase dipstick (LED). The women were treated based upon a clinical algorithm. Computer simulations explored the use of risk inclusive decision models for detection of cervical infection and/or trichomoniasis. RESULTS: Among 767 women, 206 (26.9%) had at least one STD. The prevalence of gonorrhoea was 2.7%; chlamydial infection 12.2%; gonococcal and/or chlamydial cervical infection 14.1%; trichomoniasis 11.5%; syphilis seroreactivity 5.9%. The clinical algorithm was 3.7% sensitive and 96.7% specific in detecting cervical infection. Detection of cervical infection and/or trichomoniasis was 63.5% sensitive and 60.6% specific using LED and 57.7% sensitive and 46.2% specific using the risk inclusive algorithm employed in Jamaican STD clinics. Either cervical friability or LED (+) or family planning clinic attender less than 25 years old with more than one sexual partner in the past year was 72.5% sensitive and 53.3% specific. The positive predictive values of the STD clinic algorithm, LED, and two developed decision models ranged from 25.0% to 33.4% to detect cervical infection and/or trichomoniasis in these women. CONCLUSION: STDs were quite prevalent in these mainly asymptomatic family planning clinic attenders. None of the evaluated decision models can be considered a good alternative to case detection using laboratory diagnosis. Appropriate detection tools are needed. In the meantime, available STD control strategies should be maximised, such as promotion of condom use; adequate treatment of symptomatic STD patients and partners; and education of women and men.
Adult↗
Mortality of industrial workers exposed to acrylonitrile.
OBJECTIVES: This study was designed to evaluate the relationship between occupational exposure to acrylonitrile and cancer mortality. MATERIALS AND METHODS: Workers (18079 white men, 4293 white women, 2191 nonwhite men, and 897 nonwhite women) employed in acrylonitrile production or use in the 1950s through 1983 were followed through 1989 for vital status and cause of death. Exposure-response relationships were evaluated from quantitative estimates of historical exposures. Tobacco use was determined for a sample of workers to assess potential confounding. Mortality rates between the exposed and unexposed workers in the cohort were compared using the Poisson regression. RESULTS: Analyses by cumulative, average, peak, intensity, duration, and lagged exposure revealed no elevated risk of cancers of the stomach, brain, breast, prostate or lymphatic and hematopoietic systems. Mortality from lung cancer was elevated for the highest quintile of cumulative exposure. When the decile categories were used, the relative risk did not continue to increase at higher levels. Adjustment for cigarette use reduced the risk for lung cancer only slightly. Separate analyses for wage and salaried workers, long-term and short-term workers, fiber and nonfiber plants, and individual plants revealed no clear exposure-response patterns. CONCLUSIONS: The results indicate that exposure to acrylonitrile at the levels studied is not associated with an increased relative risk for most cancers of a priori interest. The excess of lung cancer in the highest quintile of cumulative exposure may indicate carcinogenic activity at the highest levels of exposure, but analyses of exposure-response do not provide strong or consistent evidence for a causal association.
Acrylonitrile↗
The Caenorhabditis elegans gene T23G5.5 encodes an antidepressant- and cocaine-sensitive dopamine transporter.
A small subset of neurons in the nematode Caenorhabditis elegans utilizes the catecholamine dopamine (DA) as a neurotransmitter to control or modulate movement and egg-laying. Disruption of DA-mediated behaviors represents a potentially powerful strategy to identify genes that are likely to participate in dopaminergic systems in man. In vertebrates, extracellular DA is inactivated by presynaptic DA transport proteins (DATs) that are also major targets of addictive agents, including amphetamines and cocaine. We used oligonucleotides derived from the C. elegans genomic locus T23G5.5 to isolate and characterize T23G5.5 cDNAs. Our studies predict that mRNAs from this locus encode a 615-amino-acid polypeptide with twelve stretches of hydrophobicity suitable for transmembrane domains, similar to that found in vertebrate catecholamine transporters. The inferred translation product bears highest identity (43-47%) to catecholamine (DA, norepinephrine, epinephrine) transporters within the GAT1/NET gene family and possesses conserved residues implicated in amine substrate recognition. Consistent with these findings, HeLa cells transfected with the C. elegans cDNA exhibit saturable and high affinity DA transport (Km = 1.2 microM) that is dependent on extracellular Na+ and Cl- and blocked by inhibitors of mammalian catecholamine transporters, including norepinephrine transporter- and DAT-selective antagonists, tricyclic antidepressants, and the nonselective amine transporter antagonists cocaine and D-amphetamine. These studies validate the T23G5.5 locus as encoding a functional catecholamine transporter, providing important comparative sequence information for catecholamine transporter structure/function studies and a path to identify regulators of dopaminergic signaling via genetic or pharmacologic manipulation of C. elegans cDNA in vivo.
Animals↗
Is HIV/STD control in Jamaica making a difference?
OBJECTIVE: To assess the impact of the comprehensive HIV/STD Control Program established in Jamaica since the late 1980s on the HIV/AIDS epidemic. METHODS: AIDS case reports, HIV testing of blood donors, antenatal clinic attenders (ANC), food service workers, sexually transmitted disease (STD) clinic attenders, female prostitutes, homosexuals and other groups were used to monitor the HIV/AIDS epidemic. Primary and secondary syphilis and cases of congenital syphilis were also monitored. National knowledge, attitude and practice (KAP) surveys were conducted in 1988, 1989, 1992, 1994 and 1996. RESULTS: The annual AIDS incidence rate in Jamaica increased only marginally in the past three years from 18.5 per 100000 population to 21.4 in 1997. HIV prevalence in the general population groups tested has been about 1% or less. Among those at high risk, HIV prevalence rates have risen to 6.3% (95% confidence interval 5.0-8.0) in STD clinic attenders, around 10% and 21% in female prostitutes in Kingston and Montego Bay respectively and approximately 30% among homosexuals. Syphilis rates and congenital syphilis cases have declined. The proportion of men aged 15-49 years reporting sex with a non-regular partner declined from 35% in 1994 to 26% in 1996 (P< 0.001). Women ever having used condoms increased from 51% in 1988 to 62.5% in 1992 and 73% in 1994 and 1996 (P< 0.001), while condom use with a non-regular partner increased from 37% in 1992 to 73% in 1996 (P= 0.006). Condom use among men was high over the period: around 81% had ever used condoms and 77% used them with non-regular partners. Gay men, inner-city adults and adolescents aged 12-14 years all reported increases in condom use while condom sales and distribution increased from around 2 million in 1985 to 10 million in 1995. CONCLUSION: HIV/STD control measures appear to have slowed the HIV/AIDS epidemic in Jamaica, however a significant minority of persons continue to have unprotected sex in high risk situations.
Adolescent↗
Evaluation. Closing the loop.
After implementing a new nursing care delivery system, evaluating its outcomes is essential. An evaluation process answers key questions: (1) Were planned outcomes achieved? (2) Were the users satisfied? (3) Does the delivery system need to be modified?
Acute Disease↗
Incidence of HIV and HTLV-1 infection among sexually transmitted disease clinic attenders in Jamaica.
Of 970 sexually transmitted disease (STD) patients enrolled at the Comprehensive Health Centre, Kingston, Jamaica, between November 1990 and January 1991, 710 (73%, 333 men and 377 women) were reexamined between January 1992 and July 1993 to estimate the incidence of HIV and HTLV-I infection and to identify risk factors for infection. Of those reexamined, 20% were recruited passively when they returned to the clinic of their own accord, and 80% were recruited actively through field visits to their homes. Passively recruited persons were significantly more likely than active recruits to have had a sexually transmitted disease since enrollment or at their follow-up visit. Seven men and one woman became HIV positive during the period of follow-up. The overall HIV incidence rate was 0.7 per 100 person years (95% confidence interval [CI] = 0.3 to 1.4), 1.4 (CI = 0.6 to 2.8) for men and 0.2 (CI = 0.004 to 0.9) for women. Four of 270 men and 4 of 318 women were HTLV-I positive, an overall incidence of 0.9 per 100 person years (CI = 0.4 to 1.7), 1.0 for men and 0.8 for women. HTLV-I infection was associated with an age of 30 years or older (p < 0.01). The presumed lower transmission probability for HTLV-I may combine with a higher prevalence of HTLV-I in sexual partners to produce similar overall incidence rates for the two infections. The HIV and HTLV-I incidence rates may have been underestimated, because the study subjects who did not return to the clinic may have had a somewhat higher risk. On univariate analysis, there were significant associations between HIV infection in men and drinking alcohol before sex, cocaine use, total number of sex partners, sex with a prostitute since enrollment, ever accepting money for sex, the average number of sex partners per month, bruising during sex, and genital ulcers found on follow-up examination. This analysis needs to be interpreted with caution in view of the small number of seroconverters, which did not allow testing for independent effects in a logistic regression model.
Adult↗