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Biomedical subjects

H Ward

Publications and source records attributed to H Ward.

At least 19 recordsLinked to original sources
PubMed2001

The rat interleukin 10 receptor: cloning and sequencing of cDNA coding for the alpha-chain protein sequence, and demonstration by western blotting of expression in the rat brain.

cDNA coding for the alpha chain of the rat interleukin 10 (IL-10) receptor was amplified by polymerase chain reaction (PCR), cloned and sequenced. The nucleic acid coding sequence exhibited 88% and 68% homology with the mouse and human IL-10 receptor sequences, respectively. The translated protein exhibited 83% and 61% homology with the mouse and human IL-10 receptor proteins. Specific antibodies were raised to the extracellular domain of the rat IL-10 receptor expressed as a secreted protein in recombinant Drosophila S2 cells. Western blotting using these antibodies demonstrated the presence of the IL-10 receptor in five major regions of the rat brain (cortex, cerebellum, hippocampus, hypothalamus and pituitary), supporting a role for IL-10 as a central regulator of inflammation.

Amino Acid Sequence↗
PubMed2001

Geographical distribution of variant Creutzfeldt-Jakob disease in Great Britain, 1994-2000.

BACKGROUND: Geographical variation in the distribution of variant Creutzfeldt-Jakob disease (vCJD) might indicate the transmission route of the infectious agent to man. We investigated whether regional incidences of vCJD were correlated with regional dietary data. METHODS: The National CJD Surveillance Unit prospectively identified 84 people with vCJD up to Nov 10, 2000, in Great Britain. Their lifetime residential histories were obtained by interviews with a close relative. Cumulative incidences of vCJD by standard region were calculated. Grid references for places of residence in 1991 were identified and evidence of geographical clusters were sought. Data on diet in the 1980s were analysed for regional correlations with vCJD incidence. The socioeconomic status of the places of residence of people with vCJD was compared with that of the general population. FINDINGS: vCJD incidence was higher in the north of Great Britain than the south. The rate ratio (north vs south) was 1.94 (95% CI 1.27-2.98). The mean Carstairs' deprivation score for areas of residence of people with vCJD was -0.09 (-0.73 to 0.55), which is close to the national average of zero. Regional rates of vCJD were correlated with consumption of other meat or meat products as classified and recorded by the Household Food Consumption and Expenditure Survey (r=0.72), but not with data from the Dietary and Nutritional Survey of British Adults. Five people with vCJD in Leicestershire formed a cluster (p=0.004). INTERPRETATION: Regional differences in vCJD incidence are unlikely to be due to ascertainment bias. We had difficulty determining whether regional variations in diet might cause these differences, since the results of dietary analyses were inconsistent.

Adult↗
PubMed2001

Participant recruitment in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a practice-based, randomized, multicenter clinical trial in 42,419 high-risk hypertensive patients aged 55 years and older; 10,356 of these patients are also in a lipid-lowering trial component. The purpose of the antihypertensive component is to determine whether the occurrence of fatal coronary heart disease and/or nonfatal myocardial infarction differs between patients randomized to diuretic (chlorthalidone) and those randomized to either calcium antagonist (amlodipine), angiotensin-converting enzyme inhibitor (lisinopril), or alpha-adrenergic blocker (doxazosin) therapy. (The doxazosin arm has been discontinued.) The purpose of the lipid-lowering component is to determine whether lowering low-density lipoprotein cholesterol with a 3-hydroxymethyl-glutaryl coenzyme A reductase inhibitor (pravastatin) in moderately hypercholesterolemic patients will reduce all-cause mortality compared to a control group receiving "usual care." ALLHAT recruited patients from a variety of practice settings from February 1994 through January 1998. Sites were paid for randomizations and are paid for completed follow-up visits and documented study events. Communication and monitoring were facilitated by nine regional coordinator teams. It was recognized from the outset that patient recruitment would be a very large task because of the number of participants (> 40,000) needed, the ambitious nature of the goal for recruitment of African-Americans (> 55%), and the knowledge that many investigators had limited experience recruiting participants for clinical trials. Multiple adjustments in the initial ALLHAT overall recruitment plan facilitated achievement of sample size goals for both components of the trial. The experience obtained from this large trial should be valuable for the planning and implementation of successful recruitment in future trials.

Aged↗
PubMed2000

Influence of walkoff on pattern formation in nondegenerate optical parametric oscillators.

Convective and absolute nature of instabilities in nondegenerate optical parametric oscillators with large transverse section, for negative detunings and in the presence of walkoff, is examined. The asymptotic response of the signal and idler fields to a transverse localized two-dimensional perturbation is evaluated. The presence of walkoff breaks the rotational symmetry in the transverse plane, and the system, at the absolute instability threshold, selects traveling waves propagating in the walkoff direction among an infinity of unstable spatiotemporal modes. We show that in optical parametric oscillators (OPO's) with negative detunings, contrary to the case of positive detunings, the walkoff shrinks the region of convective instabilities, and even may suppress the convective/absolute transition. Hence, in a certain range of parameters, signal field envelopes in the form of wave packets of zero group velocity are found where the instability is absolute at the onset, although the walkoff is present. We also show that nonlinear pattern selection is ruled by the cross-coupling terms appearing in the asymmetric coupled Ginzburg-Landau equations derived near-threshold of the signal and idler generation. The numerical solutions of the original OPO equations confirm the analytical predictions for the values of the instability thresholds and the corresponding selected patterns.

Journal Article↗
PubMed2000

A prospective social and molecular investigation of gonococcal transmission.

BACKGROUND: Gonorrhoea is a common infectious disease, poorly controlled despite effective treatments. Tracing chains of transmission is difficult, because sexual partners are commonly difficult or impossible to identify. We assess the use of gonococcal opa-typing in identifying transmission links not revealed through interview. METHODS: Epidemiological data and gonococcal isolates were collected prospectively from patients at two UK clinics in London and Sheffield. Social and epidemiological data were combined with molecular typing of gonococcal isolates by a new methodology based on the polymorphisms of the opa gene. FINDINGS: In London, interview data and opa-typing on samples from 215 cases showed a diverse population with few links. In Sheffield, interview data identified links between 51 (43%) of 120 cases, whereas opa-typing suggested a more connected population: 95 (79%) of cases had shared profiles. There was a highly significant correlation between the two distributions with epidemiological clusters appearing as a subset of the opa clusters. Two large opa clusters, of 18 and 43 cases, accounted for 50% of local cases of gonorrhoea. Discordance between epidemiological and opa-typing data was observed at highly connected points in the sexual network. INTERPRETATION: Opa-typing is a more powerful tool for epidemiological investigation of gonorrhoea transmission than earlier methods. Opa-typing can link infections that would otherwise remain unlinked, and may aid interventions to control endemic disease.

Adolescent↗
PubMed2000

Incidence of variant Creutzfeldt-Jakob disease in the UK.

The number of deaths from variant CJD (vCJD) in the UK increased in the last quarter of 1998, although numbers were lower in subsequent quarters. We analysed the numbers of definite and probable (living and dead) vCJD cases since 1994 to assess trends in incidence. We estimated that the number of onsets increased by 23% per year for 1994-2000 (p=0.004), and that deaths increased by 33% for 1995-2000 (p=0.005). The absolute number of cases in the UK is still low, but such an increase should be a matter of concern.

Creutzfeldt-Jakob Syndrome↗
PubMed2000

Health issues associated with increasing use of "crack" cocaine among female sex workers in London.

OBJECTIVES: To document changes in "crack" cocaine use in the sex industry in London, and to assess health risks associated with the drug. DESIGN: Two serial cross sectional surveys. SUBJECTS: Sex workers interviewed in 1989-9 and 1995-6. MAIN OUTCOME MEASURES: Self reported use of crack cocaine; clinical history of sexually transmitted infection and pregnancy, clinical outcomes. RESULTS: The proportion of women reporting crack use increased significantly from 22/193 (11%) in 1989-91 to 48/143 (34%) in 1995-6. Women in all the main prostitution sectors reported crack use. Crack users had been working in prostitution for longer, were more likely to have worked on the streets, to inject drugs, and to have a partner who injected. Crack use was associated with termination of pregnancy and with hepatitis C infection. The association with hepatitis C was partially explained by confounding with injecting drug use. CONCLUSIONS: Crack use is more common and less problematic than clinical presentation suggests. Use has increased over the past decade, and is associated with hepatitis C infection and termination of pregnancy. It is possible that crack use facilitates hepatitis C transmission due to oral lesions from smoking. Crack use can be difficult to identify because of the stigma of being labelled a "crack whore," therefore information on crack might usefully be integrated into general health promotion material on drugs and safer sex.

Abortion, Induced↗
PubMed1999

Exonucleases and the incorporation of aranucleotides into DNA.

The polymerization of nucleotide analogs into DNA is a common strategy used to inhibit DNA synthesis in rapidly dividing tumor cells and viruses. The mammalian DNA polymerases catalyze the insertion of the arabinofuranosyl analogs of dNTPs (aranucleotides) into DNA efficiently, but elongate from the 3' aranucleotides poorly. Slow elongation provides an opportunity for exonucleases to remove aranucleotides. The exonuclease activity associated with DNA polymerase delta removes araCMP from 3' termini with the same efficiency that it removes a paired 3' deoxycytosine suggesting that the proofreading exonucleases associated with DNA polymerases might remove aranucleotides inefficiently. A separate 30 kDa exonuclease has been purified from mammalian cells that removes araCMP from 3' termini. The activity of this enzyme in the cell could remove aranucleotides from 3' termini of DNA and decrease the efficacy of the analogs. Inhibition analysis of the purified exonuclease shows that this enzyme is inhibited by thioinosine monophosphate (TIMP) with a Ki = 17 microM. When high TIMP levels are generated in HL-60 cells, incorporation of araC in DNA is increased about 16-fold relative to total DNA synthesis. This increased araC in DNA is likely a result of exonuclease inhibition in the cell. Thus, exonucleases in cells might play an important role in removing aranucleotides inserted by DNA polymerases.

Animals↗
PubMed1999

Risky business: health and safety in the sex industry over a 9 year period.

OBJECTIVES: To assess whether a previously established low sexually transmitted infection/HIV risk in prostitutes in London has been sustained, and to measure other occupational risks, including mortality. DESIGN: 9 year prospective study in west London. SUBJECTS: 402 prostitutes recruited from 1985 to 1991, 320 were followed up for 675 person years to 1994. MAIN OUTCOME MEASURES: Condom use in commercial and non-commercial sex; viral and bacterial sexually transmitted infection at initial and follow up visits; death. RESULTS: Condom use increased significantly from 1986 to 1993 and protected the majority of commercial sexual contacts. Baseline prevalence: HIV 1.3%, hepatitis C 6.7%, hepatitis B 6.6%, syphilis 2.3%, HTLV-I/II 0.4%, gonorrhoea 3.0%, chlamydia 8.2%, genital herpes 16.8%. Incidence (per 100 person years): HIV 0.2, hepatitis C 0.3, gonorrhoea 5.6, chlamydia 12.6, genital herpes 6.5. Viral infections were associated with injecting drug use and non-British nationality; bacterial infections were associated with numbers of non-commercial partners but not with sexual contacts at work. Four women died during the course of the study; two had AIDS, two were murdered. This mortality of 5.93 per 1000 person years was 12 times the expected rate for women of a similar age. CONCLUSIONS: This study shows that it is possible to have a larger number of sexual partners and remain free from sexually transmitted infections provided that condoms are used consistently: there has been a sustained increase in condom use in the sex industry. None the less, prostitutes are at increased risk of sexually transmitted infections, primarily through non-commercial sexual partnerships. Infectious diseases are only one of the risks facing prostitutes, as illustrated by the mortality from violence as well as from HIV infection.

Adolescent↗
PubMed1999

Impact of HIV on adult (15-54) mortality in London: 1979-96.

OBJECTIVE: To describe the impact of HIV on mortality in men and women aged 15-54 in London. DESIGN: Combination of routine mortality statistics with reports of AIDS deaths adjusted for underreporting and change in address from time of report to time of death. Calculation of standardised mortality ratios (SMRs) for males including and excluding HIV comparing inner London and outer London with the rest of England and Wales. METHODS: Comparison of trends in all cause mortality and SMRs in males over time. Comparison of trends in HIV related deaths with other main causes of deaths in males and females in London. RESULTS: Age standardised rates for the rest of England and Wales showed a continual decline from 1979 to 1996 but rates in inner London males (ages 15-54) stopped declining around 1984-5 leading to a considerable increase in the SMR for inner London from 127 for 1985-7 to 171 for 1994-6. SMRs excluding HIV related deaths for inner London, however, showed no significant change over this time. There was a fall in HIV related mortality in 1996, though HIV was still the leading cause of death in males and second leading cause of death in females in inner London, and the fourth commonest cause of death in males in outer London. CONCLUSION: These data are the first to indicate the impact of HIV on mortality within a significant population in England and Wales. They show that public health priorities in London are different from the rest of the country. Analyses of trends of all cause mortality in people under 65 may mislead unless they take account of HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Generation of a polyclonal Fab phage display library to the protozoan parasite Cryptosporidium parvum.

We had developed a technology for creation of recombinant polyclonal antibody libraries, standardized perpetual mixtures of polyclonal whole antibodies for which the genes are available and can be altered as desired. We report here the first phase of generating a polyclonal antibody library to Cryptosporidium parvum, a protozoan parasite that causes severe disease in AIDS patients, for which there is no effective treatment. BALB/c mice, immunized by neonatal oral infection with oocysts followed by intraperitoneal immunization with a sporozoite/oocyst preparation of C. parvum, were used for construction of a Fab phage display library in a specially-designed bidirectional vector. This library was selected for reactivity to an oocyst/sporozoite preparation, and was shown to be antigen-specific and diverse. Following mass transfer of the selected variable region gene pairs to appropriate mammalian expression vectors, such anti-C. parvum Fab phage display libraries could be used to develop chimeric polyclonal antibody libraries, with mouse variable regions and human constant regions, for passive immunotherapy of C. parvum infection.

Animals↗
PubMed1998

A novel multi-domain mucin-like glycoprotein of Cryptosporidium parvum mediates invasion.

Cryptosporidium parvum is a protozoan parasite which produces self-limited disease in immunocompetent hosts and devastating, persistent diarrhea in immunocompromised individuals. There is no effective treatment for cryptosporidiosis and little is known about the basic biology of the organism. Cloning and sequence analysis of the gene encoding GP900, a previously identified > 900 kDa glycoprotein, predicts a mucin-like glycoprotein composed of distal cysteine-rich domains separated by polythreonine domains and a large membrane proximal N-glycosylated core region. A trinucleotide repeat composed predominantly of the triplet ACA encodes the threonine domains. GP900 is stored in micronemes prior to appearance on the surface of invasive forms. The concentration of native GP900 which inhibits 50% (IC50) of invasion in vitro is low picomolar; the IC50 for a recombinant cysteine rich-domain is low nanomolar. These observations indicate that GP900 is a parasite ligand for a host receptor involved in attachment/invasion and suggest that immunotherapy or chemotherapy directed against GP900 may be feasible.

Amino Acid Sequence↗
PubMed1998

Ion-exchange column chromatographic method for assaying purine metabolic pathway enzymes.

High energy phosphate levels fall rapidly during cardiac ischemia and recover slowly (more than one week) during reperfusion. The slow recovery of ATP may reflect a lack of purine metabolic precursors and/or increased activity of purine catabolic enzymes such as 5'-nucleotidase (5'-NT, EC 3.1.3.5) and adenosine deaminase (ADA, EC 3.5.4.4). The activity of enzymes involved in both the catabolism of ATP precursors (5-NT and ADA) and the restoration of ATP from slow synthetic pathways [adenosine kinase (AK, EC 2.7.1.20), adenine phosphoribosyl transferase (APRT, EC 2.4.2.7) and hypoxanthine phosphoribosyl transferase (HPRT, EC 2.4.2.8)] may directly affect the rate of ATP recovery. Strategies to enhance recovery will depend on the relative activity of these enzymes following ischemia. Their activity in different species and their response to ischemia are not well characterized. Hence, rapid assay methods for these enzymes would facilitate detailed time course studies of their activities in postischemic myocardium. We modified a single ion-exchange column chromatographic method using DEAE-Sephadex to determine the products of incubation of 5'-NT, AK, APRT and HPRT with their respective substrates. The uniformity of the final product measurement procedure for all assays permits the activities of the four enzymes to be rapidly determined in a single tissue sample and facilitates the study of a large number of samples. This technique should also be useful for enzymes of the pyrimidine metabolic pathway.

5'-Nucleotidase↗
PubMed1998

Safety study of nonoxynol-9 as a vaginal microbicide: evidence of adverse effects.

Nonoxynol-9 (N-9) is virucidal in vitro, and is therefore a candidate microbicide for preventing sexual transmission of HIV. However, the activity of N-9 is nonspecific, suggesting that virucidal levels may produce adverse effects including epithelial disruption, inflammation of the genital mucosa, or both. A randomized placebo controlled trial of daily use of 100 mg of N-9 took place for 1 week in 40 female volunteers. Outcome measures included symptoms, colposcopic and histologic changes in the genital tract, and impact on vaginal flora. Genital irritation was reported by 10 of the N-9 and 5 of the placebo group. Colposcopy showed erythema in 9 of the N-9 group and 2 of the placebo group. Histologic inflammation was found in 7 of the N-9 group and 2 of the placebo group. Inflammatory changes were characterized by patchy infiltration of the lamina propria predominantly with CD8+ lymphocytes and macrophages, in the absence of epithelial disruption. A transient reduction in numbers of lactobacilli was observed in 9 of the 15 women using N-9, and 6 of 18 women using placebo. N-9 used for 7 days in a standard spermicidal dose was associated with increased irritation, colposcopic and histologic evidence of inflammation and was more frequently associated with reduction in numbers of lactobacilli during gel use. The clinical significance of the recruitment of cells susceptible to HIV infection to the genital mucosa is unknown but raises concerns about the suitability of N-9 as a microbicide when given in this dose.

Administration, Intravaginal↗