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R C Brunham

Publications and source records attributed to R C Brunham.

At least 73 records · Page 4Linked to original sources
PubMed1993

Continuous B-cell epitopes in Chlamydia trachomatis heat shock protein 60.

B-cell peptide epitopes in chlamydial heat shock protein 60 (hsp60) were elucidated with antisera from 13 rabbits immunized with Chlamydia trachomatis serovars B, C, and L2 and antisera from eight women with C. trachomatis-associated ectopic pregnancies. Thirteen major epitopes were identified with the human sera, 10 of which were also observed with rabbit antisera. Seven of the 13 epitopes recognized by human antisera exhibited cross-reactive antibody binding to homologous peptide sequences in human hsp60. Self-reactive B-cell immunity to hsp60 may contribute to chlamydial disease pathogenesis.

Amino Acid Sequence↗
PubMed1993

Antibody to Rmp (outer membrane protein 3) increases susceptibility to gonococcal infection.

The severe adverse effects of gonococcal infection on human fertility suggests that Neisseria gonorrhoeae would exert powerful selection for the development of a protective immune response in humans. N. gonorrhoeae is an obligate human pathogen and must persist in humans to survive. Since it is an ecologically successful organism, it must have evolved strategies to evade any human immune response it elicits. In a longitudinal study among 243 women working as prostitutes and experiencing frequent gonococcal infection, younger women, women with HIV infection, and women with antibody to the gonococcal outer membrane protein 3 (Rmp) were at increased risk of infection (adjusted odds ratio 3.4, CI95% 1.1-10.4, P < 0.05). Rmp is highly conserved in N. gonorrhoeae and the blocking of mucosal defences may be one of its functions. As similar proteins occur in many gram negative mucosal pathogens, the enhancing effect of such proteins may be a general strategy whereby bacteria evade human immune responses.

Adult↗
PubMed1993

The impact of HIV and other STDs on human populations. Are predictions possible?

This article presents an overview of the use of mathematical models to study the demographic impact of STDs. Written for the nonmathematician, the article introduces the basic concepts of mathematical epidemiology for infectious diseases, such as the mass-action principle, the threshold density concept, and the basic reproductive rate. Described are the main features that characterize the epidemiology of STDs and those features that differentiate them from other directly transmitted diseases, such as measles, rubella, and others. Also presented are major findings concerning the importance of sexual behavior on the dynamics of STD transmission, and the numerical analysis of the demographic impact on gonococcal and HIV infections using a mathematical model. The epidemiology of these two STDs is explored, as well as how the growth rate of the population can influence the epidemiology of these STDs. Finally, the authors demonstrate how, under some circumstances, early treatment of gonorrhea can reduce the demographic impact of HIV in regions most affected by both diseases.

Female↗
PubMed1992

Gonococcal infection, infertility, and population growth: I. Endemic states in behaviourally homogeneous growing populations.

Sexually transmitted diseases such as gonorrhoea are a significant cause of infertility in women when the infection is untreated. They have the potential to alter human population growth rates in many developing countries where sexually transmitted diseases are prevalent due to limited public health facilities for diagnosis and treatment. The authors develop a simple model describing the conditions under which such a disease can exist in a growing population in which sexual partners are chosen at random by proportionate mixing. Using the model, the impact that such a disease could have for a range of possible parameters is examined. Then a full parameter set for gonorrhoea in a developing country is estimated. Analysis demonstrates the significant influence gonococcal infection may have in reducing population growth rate in some communities. For example, the simple model predicts that a prevalence of 20% in sexually active adults results in a 50% reduction in the population growth rate. Finally, the authors discuss how potential control initiatives may change the parameter values that determine transmission and alter the demographic impact of gonorrhoea.

Africa↗
PubMed1992

Gonococcal infection, infertility, and population growth: II. The influence of heterogeneity in sexual behaviour.

Heterogeneity in sexual behaviour has an important influence on the transmission dynamics of sexually transmitted diseases (STDs). The authors describe the development of a simple mathematical model, incorporating such heterogeneity, to investigate the demographic impact of gonorrhoea on human population growth in developing countries where the disease is endemic. Earlier predictions, based on a model with homogeneous mixing, are shown to be in good qualitative agreement with the predictions of a more complex mathematical framework in which the population is stratified both by sex and into two subgroups representing low and high sexual activity, defined on the basis of rates of sexual partner change. Analyses also demonstrate that the pattern of mixing (assortative to random) between the sexual activity classes has an important influence on the predicted prevalence of gonococcal infection in a defined community. The more complex model supports earlier conclusions that gonorrhoea, via its impact on fertility, can significantly reduce net population growth rates.

Adolescent↗
PubMed1992

Chlamydia trachomatis-associated ectopic pregnancy: serologic and histologic correlates.

Fifty-five women with ectopic pregnancy and 24 undergoing tubal ligation with a segmental resection of the fallopian tube were evaluated for histopathology of the fallopian tube, Chlamydia trachomatis serum antibodies, antibodies to a chlamydial sarkosyl-soluble 57-kDa protein, and for isolation of C. trachomatis. Plasma cell infiltration in the fallopian tube submucosa was identified in 31 (65%) of 48 women with ectopic pregnancies and in 8 (33%) of 24 undergoing tubal ligation (P = .01; odds ratio [OR], 3.6; 95% confidence interval [CI], 1.3-10.3). Plasma cell infiltration was correlated with C. trachomatis seropositivity among women with ectopic pregnancy (P = .005; OR, 7.2; 95% CI, 1.7-31) and among women undergoing tubal ligation (P = .008). Of 21 C. trachomatis-seropositive women with ectopic pregnancies, 19 had antibodies to the 57-kDa antigen compared with 1 of 4 seropositive women having tubal ligation (P = .008). Immune responses to the 57-kDa antigen may be involved in the immunopathogenesis of C. trachomatis-associated ectopic pregnancy.

Adolescent↗
PubMed1992

Antigenic analysis of the chlamydial 75-kilodalton protein.

Both B- and T-cell immunogenicity of a chlamydial 75-kDa protein was analyzed by using 131 partially overlapped decapeptide homologs of the 75-kDa protein from Chlamydia trachomatis serovar L2. Six rabbit antiserum specimens raised with serovars B, C, and L2 were used to assay the antibody reactivities of the decapeptides. Seventy-five of the 131 decapeptides were recognized by at least one antiserum specimen, and two peptides were found to be immunodominant and surface accessible on native organisms. The same set of decapeptides were cleaved from the pins and tested for their T-cell-stimulating activity in an in vitro proliferation assay. A single decapeptide was able to stimulate proliferation of chlamydial antigen-primed lymph node T cells from BALB/c mice.

Amino Acid Sequence↗
PubMed1992

Antibody responses to the chlamydial heat shock proteins hsp60 and hsp70 are H-2 linked.

The effects of both H-2 and non-H-2 genes on antibody responses to two Chlamydia trachomatis heat shock proteins (hsp60 and hsp70) were investigated. These chlamydial proteins are homologs of Escherichia coli GroEL (hsp60) and DnaK (hsp70) and are highly sequence conserved between bacterial and mammalian sources. Antibody responses among 17 different strains of mice immunized with C. trachomatis serovar B and serovar C elementary bodies were evaluated by immunoblot, radioimmunoprecipitation and enzyme-linked immunosorbent assay. Antibody responses to the two proteins displayed host genetic restriction. Of six distinctive H-2 haplotypes, only H-2d generated high antibody responses to hsp70. Five of the six H-2 haplotypes, i.e., H-2a, H-2d, H-2k, H-2q, and H-2s, produced high antibody responses to hsp60. Only the H-2b-bearing strain had low antibody responses to hsp60. By using congenic and H-2 recombinant strains, the genes responsible for regulating antibody responses to hsp70 and hsp60 were mapped to the K-IA region of the H-2 locus. In F1 hybrid crosses between high and low responders, high responses to hsp60 and hsp70 were dominant traits. Other genes outside the H-2 locus also influenced antibody responses to hsp60 and hsp70, since inbred strains of identical H-2 but different background genes displayed variable antibody responses to the proteins. The genetic control of murine immune responses to C. trachomatis hsp60, a putative chlamydial immunopathologic antigen, suggests that a similar genetic mechanism may also exist in humans, and this observation may help to explain the observed variability in the spectrum of chlamydial diseases seen in humans.

Animals↗
PubMed1992

Acquisition and synthesis of folates by obligate intracellular bacteria of the genus Chlamydia.

We undertook studies focused on folate acquisition by Chlamydia trachomatis L2, Chlamydia psittaci 6BC, and C. psittaci francis. Results from in situ studies, using wild-type host cells, confirmed that C. trachomatis L2 and C. psittaci 6BC are sensitive to sulfonamides whereas C. psittaci francis is resistant. In addition C. trachomatis L2 and C. psittaci francis were inhibited by methotrexate in situ whereas C. psittaci 6BC was not. In contrast to C. trachomatis, neither C. psittaci strain was affected by trimethoprim. Surprisingly our results indicate that all three strains are capable of efficient growth in folate-depleted host cells. When growing in folate-depleted cells C. psittaci francis becomes sensitive to sulfonamide. The ability of all three strains to carry out de novo folate synthesis was demonstrated by following the incorporation of exogenous [3H]pABA into intracellular folates and by detecting dihydropteroate synthase activity in reticulate body crude extract. Dihydrofolate reductase activity was also detected in reticulate body extract. In aggregate the results indicate that C. trachomatis L2, C. psittaci francis, and C. psittaci 6BC can all synthesize folates de novo, however, strains differ in their ability to transport preformed folates directly from the host cell.

4-Aminobenzoic Acid↗
PubMed1992

The role of the laboratory in a Chlamydia control programme in a developing country.

The laboratory components of a Chlamydia trachomatis disease control programme for a developing country are reviewed. Early diagnosis of chlamydial infections is the most cost effective means of preventing the long term sequelae of trachoma, pelvic inflammatory disease, ectopic pregnancy and infertility, which are now a major public health burden to the health care system in developing countries. Public health strategies are required to establish both a co-ordinated limited system of laboratory services, and to promote the diagnosis and treatment of disease syndromes in the absence of laboratory support. Laboratory tests for the specific diagnoses of chlamydial infections requiring different levels of expertise and equipment can be instituted within settings appropriate to the resources and technical expertise available. Emphasis is given to appropriate cost effective utilization of laboratory testing.

Chlamydia Infections↗
PubMed1991

Gonococcal infection and human fertility in sub-Saharan Africa.

An analysis is presented of the influence of Neisseria gonorrhoeae on human population growth in regions of sub-Saharan Africa where gonococcal infections are prevalent in sexually active adults. Combining epidemiological and demographic data within the framework of a mathematical model, we show that gonorrhoea has a major impact on fertility and, concomitantly, on net population growth in areas with a high prevalence of untreated infections. Specifically, a 20% prevalence in sexually active adults is predicted to induce a 50% reduction in net population growth. Model predictions are in good agreement with observed data from Uganda, and the sensitivity of the prediction to various complications, such as heterogeneity in sexual behaviour, is assessed. The analysis suggests that the predicted increase in fertility arising from expanded sexually transmitted disease (STD) control programmes in Africa to help combat the spread of human immunodeficiency viruses (HIV-1 and HIV-2) will help to offset the predicted demographic impact of AIDS in the worst afflicted areas. In other areas the rise in fertility associated with effective STD control will need to be countered by the linkage of STD control programmes with family planning initiatives.

Adolescent↗
PubMed1991

Treatment of acute pelvic inflammatory disease in the ambulatory setting: trial of cefoxitin and doxycycline versus ampicillin-sulbactam.

Ampicillin-sulbactam (750 mg) given orally twice daily for 10 days was evaluated for the treatment of acute pelvic inflammatory disease (PID) in an ambulatory setting in Nairobi, Kenya. The first 26 women received ampicillin-sulbactam in an open-label fashion, and the remaining 75 women were randomly selected to receive either ampicillin-sulbactam (n = 38) or cefoxitin (2 g) intramuscularly and probenecid (1 g) orally, followed by doxycycline (100 mg) orally twice daily for 10 days (n = 37). Women were enrolled in a sexually transmitted disease clinic and were followed for clinical and microbiologic responses at 1 to 2 weeks and 4 to 6 weeks posttreatment. Women had a later follow-up visit to note interim pregnancy or underwent hysterosalpingography for fertility outcome assessment. The short-term clinical response rates were 70% for ampicillin-sulbactam and 72% for cefoxitin-doxycycline (P = 0.47). Among Chlamydia trachomatis-infected women treated with ampicillin-sulbactam, three had microbiologic relapse. The post-PID tubal obstruction rates were similar in the two groups: 18% for ampicillin-sulbactam and 33% for cefoxitin-doxycycline (P = 0.31). Neither regimen was highly effective as a therapy for acute PID. These data strongly argue that primary prevention must be the goal for a reduction of PID morbidity and show that improved therapy for the treatment of PID in the ambulatory setting is needed.

Acute Disease↗
PubMed1991

Antigenic determinants of the chlamydial major outer membrane protein resolved at a single amino acid level.

Antigenic determinants were identified from seven chlamydial major outer membrane proteins by using overlapping hexapeptides and polyclonal antisera. Sixty-one determinants were detected, and 30 were surface exposed on the native organisms. The two negatively charged residues, aspartic acid and glutamic acid, were found most often in determinants. Thirteen antigenic sites were further characterized by alanine substitution. Differences in fine specificities of these linear determinants were observed in alanine substitution profiles. Five determinants had adjacent critical residues, while eight had critical residues alternated with noncritical residues. Complete replacement analysis of two antigenic determinants provided more detailed information for elucidating the structural basis of the specificity of antigen-antibody interaction and suggested a correlation between sequence conservation and tolerance to amino acid substitution for antigenic sites subject to intense immune selection pressure.

Alanine↗
PubMed1991

Neutralization of Chlamydia trachomatis: kinetics and stoichiometry.

Monoclonal antibodies to the major outer membrane protein of Chlamydia trachomatis were used to neutralize C. trachomatis infectivity in HeLa 229 cells and to determine the kinetics and stoichiometry of the reaction. In vitro neutralization of C. trachomatis infectivity proceeded as a first-order reaction and required an activation energy of approximately 20 kcal/mol (ca. 84 kJ/mol). The rate of neutralization was linear with respect to antibody concentration and reaction temperature. The efficiency of neutralization decreased exponentially as the ratio of noninfective to infective chlamydiae increased in the antigen preparation. The neutralization assay was also significantly affected by reaction parameters such as the reaction volume and the duration of incubation. Stoichiometric calculations showed that an average ratio of 10(3) and 10(4) immunoglobulin molecules per chlamydial particle was required to yield 50% neutralization by monoclonal antibodies specifying serovar-specific and species-specific epitopes, respectively. The implications of these findings for vaccine design and for the role of the major outer membrane protein in the pathogenesis of chlamydial infections are discussed.

Antibodies, Monoclonal↗
PubMed1991

Biochemical evidence for the existence of thymidylate synthase in the obligate intracellular parasite Chlamydia trachomatis.

Since eucaryotic cell-derived thymidine or thymidine nucleotides are not incorporated into Chlamydia trachomatis DNA, we hypothesized that C. trachomatis must obtain dTTP for DNA synthesis by converting dUMP to dTMP. In most cells, this reaction is catalyzed by thymidylate synthase (TS) and requires 5,10-methylenetetrahydrofolate as a cofactor. We used C. trachomatis serovar L2 and a mutant CHO K1 cell line with a genetic deficiency in folate metabolism as a host for chlamydial growth. This cell line lacks a functional dihydrofolate reductase (DHFR) gene and, as a result, is unable to carry out de novo synthesis of dTTP. C. trachomatis inclusions form normally when DHFR- cells are starved for thymidine 24 h prior to and during the course of infection. When [6-3H]uridine is used as a precursor to label C. trachomatis-infected CHO DHFR- cells, radiolabel is readily incorporated into chlamydia-specific DNA. When DNA from [6-3H]uridine-labelled infected cultures is acid hydrolyzed and subjected to high-performance liquid chromatography analysis, radiolabel is detected in thymine and cytosine nucleobases. By using the DHFR- cell line as a host and [5-3H]uridine as a precursor, we could monitor intracellular C. trachomatis TS activity simply by following the formation of tritiated water. There is a good correlation between in situ TS activity and DNA synthesis activity during the chlamydial growth cycle. In addition, both C. trachomatis-specific DNA synthesis and 3H2O release are inhibited by exogenously added 5-fluorouridine but not by 5-fluorodeoxyuridine. Finally, we demonstrated in vitro TS activity in crude extracts prepared from highly purified C. trachomatis reticulate bodies. The activity is dependent on the presence of methylenetetrahydrofolic acid and can be inhibited with 5-fluoro-dUMP. Taken together, these results indicate that C. trachomatis contains a TS for the synthesis of dTMP.

Animals↗
PubMed1990

Rapid control of a chancroid outbreak: implications for Canada.

From June to November 1987 an outbreak of chancroid occurred in Winnipeg, the first in more than 10 years; 14 people (9 men, 5 women) were involved. Nine of the cases were confirmed through culture. A control strategy was implemented in November 1987 that included presumptive treatment of genital ulcer disease with single-dose antimicrobial therapy, intensive tracing of contacts and treatment of asymptomatic sexual contacts. The origin of the outbreak was not determined, and an epidemiologic link between all the patients could not be demonstrated. The isolates were found to contain the same plasmid; this suggested that a single clone of Haemophilus ducreyi was responsible for the outbreak.

Adult↗