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1.  Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses. 
A40926 is a new glycopeptide antibiotic with unique activity against Neisseria gonorrhoeae and high and prolonged levels in mouse blood (B. P. Goldstein, E. Selva, L. Gastaldo, M. Berti, R. Pallanza, F. Ripamonti, P. Ferrari, M. Denaro, V. Arioli, and G. Cassani, Antimicrob. Agents Chemother., 31:1961-1966, 1987). We studied the pharmacokinetics of A40926 in rats after single intravenous and subcutaneous 10-mg/kg (body weight) doses. Concentrations in plasma and urine were determined by microbiological assay. After intravenous administration, high concentrations of A40926, ranging from 132 mg/liter at 3 min to 0.7 mg/liter at 96 h, were found in plasma. Concentrations declined with a three-exponential decay correlated with a prolonged, biphasic distribution and a slow elimination (terminal half-life, 61.22 h). After completion of the distribution, the compound was widely distributed to the extravascular space. The rate-limiting step in the elimination of A40926 from the body appears to be the slow return from the deep compartment into the central one. A40926 was rapidly absorbed from the injection site after subcutaneous administration, and its availability was close to 90%. The percentage of the dose excreted in urine in 120 h was 35.9%.
PMCID: PMC172143  PMID: 3364946
2.  Sensitivity of Gram-negative bacilli to ampicillin after six years' clinical use 
Journal of Clinical Pathology  1969;22(6):644-648.
A total of 1,102 clinical isolates of Gram-negative bacilli was obtained from four hospitals during 1967 and these cultures were tested for sensitivity to ampicillin. Approximately 80% of the strains of Escherichia coli and 90% of the strains of Proteus mirabilis, the two organisms most frequently isolated, were sensitive to ampicillin. Klebsiella-Enterobacter species and Pseudomonas aeruginosa were generally insensitive. Comparison of these results with data obtained in an earlier study with Gram-negative organisms isolated in 1961 showed that there had been no significant increase in the incidence of resistance of Gram-negative bacilli to ampicillin during the period 1961-67.
The majority of ampicillin-resistant strains of E. coli isolated in 1967 transferred ampicillin resistance to a sensitive strain of E. coli K12. Only four ampicillin-resistant strains of E. coli isolated in 1961 were available for transferable resistance tests but all four strains transferred ampicillin resistance. Infective or transferable resistance was therefore a feature of ampicillin resistance of certain Gram-negative bacteria before ampicillin became generally available for clinical use.
PMCID: PMC474333  PMID: 4983462
3.  The incidence of Down's syndrome over a 19-year period with special reference to maternal age. 
Journal of Medical Genetics  1983;20(2):90-93.
The incidence of Down's syndrome in the Liverpool and Bootle areas from 1961 to 1979 was investigated. A total of 319 liveborn cases was ascertained over this period. Using 3-year moving averages, the incidence of the condition fell gradually from 1.62 per 1000 livebirths for 1961 to 1963 to 1.09 per 1000 livebirths for 1977 to 1979. This trend is significant at the 0.1% level. Over the same period the mean maternal age of Down's syndrome births fell gradually from 36.7 years in 1961 to 29.0 years in 1979. This trend is significant at the 1% level. There was a contemporaneous decrease in the proportion of total births to women over 35 years in the study area. Cytogenetic analysis was performed on 175 out of the 319 index cases (54.9%). Of these, there were 161 trisomies (92%), 11 translocations (6.3%), and three mosaics (1.7%). Between 1969 and 1979 four terminations of pregnancy for Down's syndrome were performed, all for trisomy. Quinquennial age specific incidences for Down's syndrome were calculated for the years 1960 to 1964, 1965 to 1969, 1970 to 1974, and 1975 to 1979. There have been no statistically significant changes over this time. It is suggested that the fall in incidence of Down's syndrome can be explained by the fall in mean maternal age.
PMCID: PMC1049005  PMID: 6221104
4.  Temporal trends in non-small cell lung cancer survival in Sweden 
British Journal of Cancer  2007;96(3):519-522.
We modeled temporal trends in the 1- and 5-year survival of 32 499 patients with adenocarcinoma and squamous cell carcinoma of the lung in the Swedish Cancer Register between 1961 and 2000. The 1-year relative survival for adenocarcinoma improved from 37% for patients diagnosed 1961–1965 to 45% for those diagnosed 1996–2000 and from 39 to 45% for squamous cell carcinoma. The adjusted excess mortality ratios for the period 1996–2000 compared with 1961–1965 were 0.80 for adenocarcinoma and 0.81 for squamous cell carcinoma. Thus, a previous report in a Dutch study of a relatively worsening prognosis for adenocarcinoma over time could not be confirmed.
PMCID: PMC2360026  PMID: 17245337
lung cancer; adenocarcinoma; squamous cell carcinoma; survival, Sweden
5.  On the utility of the lognormal model for analysis of breast cancer survival in Sweden 1961-1973. 
British Journal of Cancer  1985;52(6):875-883.
Parametric models have been suggested as an alternative to conventional life table techniques for interpretation of observed survival patterns in cancer. This paper extends earlier work on breast cancer by studying the fit of Boag's lognormal model to the survival of 8,170 breast cancer cases reported to the Swedish Cancer Registry during 1961-1963. The model was also used to analyse the upward survival trend for breast cancer cases in Sweden during 1961-1973. The model fitted the 1961-1963 data well for the entire case material and for patients aged less than 70 years. It was therefore used to help explain whether the upward survival trend was due to long term cures or merely to protracted survival with cancer. The estimated cured proportion among patients aged less than 70 years rose from 33% +/- 2% (s.e.) during 1961-1963 to 40% +/- 3% for cases 1971-1973 (P less than 0.05). The median survival of uncured cases, was found to be similar during both periods, 4.5 and 4.6 years respectively. The model did not fit data for patients aged greater than 70 years. It is possibly too simplistic, and perhaps does not accurately describe the forces of mortality or their interactions in old patients. Another disadvantage is that large case materials are necessary in order to obtain estimates with reasonably small standard errors.
PMCID: PMC1977276  PMID: 4074639
6.  Genome, Integration, and Transduction of a Novel Temperate Phage of Helicobacter pylori 
Journal of Virology  2012;86(16):8781-8792.
Helicobacter pylori is a common human pathogen that has been identified to be carcinogenic. This study isolated the temperate bacteriophage 1961P from the lysate of a clinical strain of H. pylori isolated in Taiwan. The bacteriophage has an icosahedral head and a short tail, typical of the Podoviridae family. Its double-stranded DNA genome is 26,836 bp long and has 33 open reading frames. Only 9 of the predicted proteins have homologs of known functions, while the remaining 24 are only similar to unknown proteins encoded by Helicobacter prophages and remnants. Analysis of sequences proximal to the phage-host junctions suggests that 1961P may integrate into the host chromosome via a mechanism similar to that of bacteriophage lambda. In addition, 1961P is capable of generalized transduction. To the best of our knowledge, this is the first report of the isolation, characterization, genome analysis, integration, and transduction of a Helicobacter pylori phage.
PMCID: PMC3421732  PMID: 22696647
7.  Antimicrobial susceptibility/resistance and genetic characteristics of Neisseria gonorrhoeae isolates from Poland, 2010-2012 
In Poland, gonorrhoea has been a mandatorily reported infection since 1948, however, the reported incidences are likely underestimated. No antimicrobial resistance (AMR) data for Neisseria gonorrhoeae has been internationally reported in nearly four decades, and data concerning genetic characteristics of N. gonorrhoeae are totally lacking. The aims of this study were to investigate the AMR to previously and currently recommended gonorrhoea treatment options, the main genetic resistance determinant (penA) for extended-spectrum cephalosporins (ESCs), and genotypic distribution of N. gonorrhoeae isolates in Poland in 2010-2012.
N. gonorrhoeae isolates cultured in 2010 (n = 28), 2011 (n = 92) and 2012 (n = 108) in Warsaw and Bialystok, Poland, were examined using antimicrobial susceptibility testing (Etest), pyrosequencing of penA and N. gonorrhoeae multi-antigen sequence typing (NG-MAST).
The proportions of N. gonorrhoeae isolates showing resistance were as follows: ciprofloxacin 61%, tetracycline 43%, penicillin G 22%, and azithromycin 8.8%. No isolates resistant to ceftriaxone, cefixime or spectinomycin were found. However, the proportion of isolates with an ESC MIC = 0.125 mg/L, i.e. at the resistance breakpoint, increased significantly from none in 2010 to 9.3% and 19% in 2012 for ceftriaxone and cefixime, respectively. Furthermore, 3.1% of the isolates showed multidrug resistance, i.e., resistance to ciprofloxacin, penicillin G, azithromycin, and decreased susceptibility to cefixime (MIC = 0.125 mg/L). Seventy-six isolates (33%) possessed a penA mosaic allele and 14 isolates (6.1%) contained an A501V/T alteration in penicillin-binding protein 2. NG-MAST ST1407 (n = 58, 25% of isolates) was the most prevalent ST, which significantly increased from 2010 (n = 0) to 2012 (n = 46; 43%).
In Poland, the diversified gonococcal population displayed a high resistance to most antimicrobials internationally previously recommended for gonorrhoea treatment and decreasing susceptibility to the currently recommended ESCs. The decreasing susceptibility to ESCs was mostly due to the introduction of the internationally spread multidrug-resistant NG-MAST ST1407 in 2011. It is essential to promptly revise the gonorrhoea treatment guidelines, improve the gonorrhoea laboratory diagnostics, and implement quality assured surveillance of gonococcal AMR (ideally also treatment failures) in Poland.
PMCID: PMC3922028  PMID: 24502606
Neisseria gonorrhoeae; Gonorrhoea; Poland; Antimicrobial resistance (AMR); Extended-spectrum cephalosporins (ESCs); Ceftriaxone; Cefixime; penA; NG-MAST
8.  Phenotypic and genetic characterisation of bacterial sexually transmitted infections in Bissau, Guinea-Bissau, West Africa: a prospective cohort study 
BMJ Open  2012;2(2):e000636.
Knowledge regarding characteristics and transmission of Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium and antibiotic resistance in N gonorrhoeae in Guinea-Bissau, West Africa, is entirely lacking.
To characterise N gonorrhoeae, C trachomatis and M genitalium samples from Guinea-Bissau and to define bacterial populations, possible transmission chains and for N gonorrhoeae spread of antibiotic-resistant isolates.
Prospective cohort study.
Two sexual health and family planning clinics, Bissau, Guinea-Bissau.
Positive samples from 711 women and 27 men.
Material and methods
Positive samples for N gonorrhoeae (n=31), C trachomatis (n=60) and M genitalium (n=30) were examined. The gonococcal isolates were characterised with antibiograms, serovar determination and N gonorrhoeae multiantigen sequence typing (NG-MAST). The C trachomatis ompA gene and the M genitalium mgpB gene were sequenced, and phylogenetic analyses were performed.
For N gonorrhoeae, the levels of resistance (intermediate susceptibility) to ciprofloxacin, erythromycin, rifampicin, ampicillin, tetracycline, penicillin G and cefuroxime were 10% (0%), 6% (10%), 13% (10%), 68% (0%), 74% (0%), 68% (16%) and 0% (84%), respectively. All isolates were susceptible to cefixime, ceftriaxone, spectinomycin and azithromycin, and the minimum inhibitory concentrations of kanamycin (range: 8–32 mg/l) and gentamicin (range: 0.75–6 mg/l) were low (no resistance breakpoints exist for these antimicrobials). 19 NG-MAST sequence types (STs) (84% novel STs) were identified. Phylogenetic analysis of the C trachomatis ompA gene revealed genovar G as most prevalent (37%), followed by genovar D (19%). 23 mgpB STs were found among the M genitalium isolates, and 67% of isolates had unique STs.
The diversity among the sexually transmitted infection (STI) pathogens may be associated with suboptimal diagnostics, contact tracing, case reporting and epidemiological surveillance. In Guinea-Bissau, additional STI studies are vital to estimate the STI burden and form the basis for a national sexual health strategy for prevention, diagnosis and surveillance of STIs.
Article summary
Article focus
Knowledge regarding characteristics and transmission of Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium and antibiotic resistance in N gonorrhoeae in Guinea-Bissau, West Africa, is entirely lacking.
We aimed to phenotypically and genetically characterise N gonorrhoeae, and genetically characterise C trachomatis and M genitalium samples from women attending two sexual health clinics in Bissau, Guinea-Bissau and to define the bacterial populations, possible transmission chains and for N gonorrhoeae also to define the presence and spread of antibiotic-resistant isolates from women and additionally a group of symptomatic men.
Key messages
In Guinea-Bissau, N gonorrhoeae isolates displayed high level of resistance to traditional gonorrhoea antimicrobials but have remained susceptible to extended-spectrum cephalosporins, spectinomycin and azithromycin.
Genovar G, D and F were the most prevalent C trachomatis genovars, the usually most common genovar among heterosexuals, that is, genovar E, was rare.
The diversity among the bacterial STI pathogens may be associated with suboptimal diagnostics, contact tracing, case reporting and epidemiological surveillance. Additional studies are vital to estimate the STI burden and form the basis for a national sexual health strategy for prevention, diagnosis and surveillance.
Strengths and limitations of this study
This is the first time N gonorrhoeae, C trachomatis and M genitalium samples from Bissau, Guinea-Bissau, have been phenotypically and genetically characterised to define the bacterial populations, possible transmission chains and antibiotic resistance in N gonorrhoeae.
The study sample was relatively small, and in this setting, it is difficult to perform appropriate sample transportation and storage, as well as optimised diagnostics, which may have resulted in that true-positive samples were lost.
PMCID: PMC3329603  PMID: 22436137
9.  Treating genitourinary and pharyngeal gonorrhoea with single dose ceftriaxone. 
Genitourinary Medicine  1989;65(1):14-17.
The efficacy of ceftriaxone 250 mg given as a single intramuscular dose to treat genitourinary and pharyngeal gonorrhoea is compared with the outcome of the Danish standard treatment for uncomplicated genitourinary gonorrhoea, pivampicillin 1.4 g and probenecid 1 g, both given by mouth. The study comprised 327 patients for whom the diagnosis of gonorrhoea was made by microscopy of a methylene blue stained smear at their first visit to the clinic and for whom the diagnosis was later confirmed by culture of Neisseria gonorrhoeae. One hundred and seventy patients with genitourinary gonorrhoea (18 with and 152 without concomitant pharyngeal infection) were treated with ceftriaxone. One hundred and fifty seven (17 with and 140 without concomitant pharyngeal infection) were treated with pivampicillin. One week after treatment N gonorrhoeae was isolated from none of 18, 1/152, (1%), 11/17 (65%), and 6/140 (4%) patients, respectively. At a second attendance two weeks after treatment no further treatment failure was found. During the study period, a further 52 patients with pharyngeal infection (with or without concomitant genitourinary infection) that was shown by culture only were treated with a single intramuscular injection of 250 mg ceftriaxone. No treatment failure was observed in this group. Only minor adverse drug reactions were seen. Ceftriaxone 250 mg as a single intramuscular injection is therefore safe and effective in treating gonorrhoea, including pharyngeal infection.
PMCID: PMC1196180  PMID: 2921047
10.  Monitoring Antimicrobial Susceptibility of Neisseria gonorrhoeae Isolated from Bangladesh during 1997-2006: Emergence and Pattern of Drug-resistant Isolates 
Gonorrhoea is one of the most common sexually transmitted infections (STIs) in developing countries, and the emergence of resistance to antimicrobial agents in Neisseria gonorrhoeae is a major obstacle in the control of gonorrhoea. Periodical monitoring of antimicrobial susceptibility of N. gonorrhoeae is essential for the early detection of emergence of drug resistance. In total, 1,767 gonococcal strains isolated from males and females (general population and those with high-risk behaviour) from different parts of Bangladesh were studied during 1997-2006. Minimum inhibitory concentrations of penicillin, tetracycline, ciprofloxacin, ceftriaxone, spectinomycin, and azithromycin for the isolates were determined by the agar dilution method. Isolates resistant to three or more antimicrobial agents are considered multidrug-resistant. The prevalence of plasmid-mediated penicillinase-producing N. gonorrhoeae (PPNG) and plasmid-mediated tetracycline-resistant N. gonorrhoeae (TRNG) was determined. Nine percent of the isolates were resistant to ciprofloxacin in 1997 compared to 87% in 2006. Multidrug-resistant N. gonorrhoeae have emerged in 1997, and 44% of the strains (n=66) isolated during 2006 were multidrug-resistant. Forty-two percent of the isolates in 2006 were both PPNG- and TRNG-positive compared to none in 1997. The rapidly-changing pattern of gonococcal antimicrobial susceptibility warrants the need for an antimicrobial susceptibility-monitoring programme, and periodical analysis and dissemination of susceptibility data are essential to guide clinicians and for successful STI/HIV intervention programmes.
PMCID: PMC2963766  PMID: 20941895
Drug resistance, Microbial; Gonorrhoea; Neisseria gonorrhoeae; Sexually transmitted infections; Surveillance; Bangladesh
11.  Neisseria gonorrhoeae Induces a Tolerogenic Phenotype in Macrophages to Modulate Host Immunity 
Mediators of Inflammation  2013;2013:127017.
Neisseria gonorrhoeae is the etiological agent of gonorrhoea, which is a sexually transmitted disease widespread throughout the world. N. gonorrhoeae does not improve immune response in patients with reinfection, suggesting that gonococcus displays several mechanisms to evade immune response and survive in the host. N. gonorrhoeae is able to suppress the protective immune response at different levels, such as B and T lymphocytes and dendritic cells. In this study, we determined whether N. gonorrhoeae directly conditions the phenotype of RAW 264.7 murine macrophage cell line and its response. We established that gonococcus was effectively phagocytosed by the RAW 264.7 cells and upregulates production of immunoregulatory cytokines (IL-10 and TGF-β1) but not the production of proinflammatory cytokine TNF-α, indicating that gonococcus induces a shift towards anti-inflammatory cytokine production. Moreover, N. gonorrhoeae did not induce significant upregulation of costimulatory CD86 and MHC class II molecules. We also showed that N. gonorrhoeae infected macrophage cell line fails to elicit proliferative CD4+ response. This implies that macrophage that can phagocytose gonococcus do not display proper antigen-presenting functions. These results indicate that N. gonorrhoeae induces a tolerogenic phenotype in antigen-presenting cells, which seems to be one of the mechanisms to induce evasion of immune response.
PMCID: PMC3800590  PMID: 24204097
12.  Chlamydial and gonococcal reinfection among men: a systematic review of data to evaluate the need for retesting 
Sexually Transmitted Infections  2006;83(4):304-309.
This study aimed to systematically review and describe the evidence on chlamydia and gonorrhoea reinfection among men, and to evaluate the need for retesting recommendations in men. PubMed and STI conference abstract books from January 1995 to October 2006 were searched to identify studies on chlamydia and gonorrhoea reinfection among men using chlamydia and gonorrhoea nucleic acid amplification tests or gonorrhoea culture. Studies were categorised as using either active or passive follow‐up methods. The proportions of chlamydial and gonococcal reinfection among men were calculated for each study and summary medians were reported. Repeat chlamydia infection among men had a median reinfection probability of 11.3%. Repeat gonorrhoea infection among men had a median reinfection probability of 7.0%. Studies with active follow‐up had moderate rates of chlamydia and gonorrhoea reinfection among men, with respective medians of 10.9% and 7.0%. Studies with passive follow‐up had higher proportions of both chlamydia and gonorrhoea reinfections among men, with respective medians of 17.4% and 8.5%. Proportions of chlamydia and gonorrhoea reinfection among men were comparable with those among women. Reinfection among men was strongly associated with previous history of sexually transmitted diseases and younger age, and inconsistently associated with risky sexual behaviour. Substantial repeat chlamydia and gonorrhoea infection rates were found in men comparable with those in women. Retesting recommendations in men are appropriate, given the high rate of reinfection. To optimise retesting guidelines, further research to determine effective retesting methods and establish factors associated with reinfection among men is suggested.
PMCID: PMC2598678  PMID: 17166889
13.  Reducing the risk of gonorrhoea in black Caribbean men: can we identify risk factors? 
Sexually Transmitted Infections  2003;79(2):119-123.
Objectives: Grouping patients by self assigned ethnicity may hide intraethnic differences in disease associations and sexual behaviour patterns. The aim of the study was to detect associations between gonorrhoea with differences in ancestry, degree of acculturation, and religious belief in young black Caribbean men, which could subsequently be used to target health promotion interventions.
Methods: A questionnaire based case-control study of black Caribbean men with gonorrhoea and a community control group without gonorrhoea.
Results: A lesser degree of acculturation, attending a single sex school, increasing numbers of partners, lack of condom use, not being married, and a belief that sex before marriage was not wrong were associated with an increased risk of gonorrhoea. Country of birth and religious belief were not associated with gonorrhoea.
Conclusions: A number of factors were identified which may be useful in designing healthcare interventions in young black Caribbean men and these differed little from those in other ethnic groups. The healthcare intervention should include advice on reducing the number of partners and increasing the use of condoms.
PMCID: PMC1744632  PMID: 12690132
14.  Biofilm Formation by Neisseria gonorrhoeae  
Infection and Immunity  2005;73(4):1964-1970.
Studies were performed in continuous-flow chambers to determine whether Neisseria gonorrhoeae could form a biofilm. Under these growth conditions, N. gonorrhoeae formed a biofilm with or without the addition of 10 μM sodium nitrite to the perfusion medium. Microscopic analysis of a 4-day growth of N. gonorrhoeae strain 1291 revealed evidence of a biofilm with organisms embedded in matrix, which was interlaced with water channels. N. gonorrhoeae strains MS11 and FA1090 were found to also form biofilms under the same growth conditions. Cryofield emission scanning electron microscopy and transmission electron microscopy confirmed that organisms were embedded in a continuous matrix with membranous structures spanning the biofilm. These studies also demonstrated that N. gonorrhoeae has the capability to form a matrix in the presence and absence of CMP-N-acetylneuraminic acid (CMP-Neu5Ac). Studies with monoclonal antibody 6B4 and the lectins soy bean agglutinin and Maackia amurensis indicated that the predominate terminal sugars in the biofilm matrix formed a lactosamine when the biofilm was grown in the absence of CMP-Neu5Ac and sialyllactosamine in the presence of CMP-Neu5Ac. N. gonorrhoeae strain 1291 formed a biofilm on primary urethral epithelial cells and cervical cells in culture without loss of viability of the epithelial cell layer. Our studies demonstrated that N. gonorrhoeae can form biofilms in continuous-flow chambers and on living cells. Studies of these biofilms may have implications for understanding asymptomatic gonococcal infection.
PMCID: PMC1087446  PMID: 15784536
15.  Neisseria gonorrhoeae Infection Protects Human Endocervical Epithelial Cells from Apoptosis via Expression of Host Antiapoptotic Proteins▿ † 
Infection and Immunity  2009;77(9):3602-3610.
Several microbial pathogens can modulate the host apoptotic response to infection, which may contribute to immune evasion. Various studies have reported that infection with the sexually transmitted disease pathogen Neisseria gonorrhoeae can either inhibit or induce apoptosis. N. gonorrhoeae infection initiates at the mucosal epithelium, and in women, cells from the ectocervix and endocervix are among the first host cells encountered by this pathogen. In this study, we defined the antiapoptotic effect of N. gonorrhoeae infection in human endocervical epithelial cells (End/E6E7 cells). We first established that N. gonorrhoeae strain FA1090B failed to induce cell death in End/E6E7 cells. Subsequently, we demonstrated that stimulation with N. gonorrhoeae protected these cells from staurosporine (STS)-induced apoptosis. Importantly, only End/E6E7 cells incubated with live bacteria and in direct association with N. gonorrhoeae were protected from STS-induced apoptosis, while heat-killed and antibiotic-killed bacteria failed to induce protection. Stimulation of End/E6E7 cells with live N. gonorrhoeae induced NF-κB activation and resulted in increased gene expression of the NF-κB-regulated antiapoptotic genes bfl-1, cIAP-2, and c-FLIP. Furthermore, cIAP-2 protein levels also increased in End/E6E7 cells incubated with gonococci. Collectively, our results indicate that the antiapoptotic effect of N. gonorrhoeae in human endocervical epithelial cells results from live infection via expression of host antiapoptotic proteins. Securing an intracellular niche through the inhibition of apoptosis may be an important mechanism utilized by N. gonorrhoeae for microbial survival and immune evasion in cervical epithelial cells.
PMCID: PMC2738021  PMID: 19546192
16.  A bacterial PriB with weak single-stranded DNA binding activity can stimulate the DNA unwinding activity of its cognate PriA helicase 
BMC Microbiology  2011;11:189.
Bacterial DNA replication restart pathways facilitate reinitiation of DNA replication following disruptive encounters of a replisome with DNA damage, thereby allowing complete and faithful duplication of the genome. In Neisseria gonorrhoeae, the primosome proteins that catalyze DNA replication restart differ from the well-studied primosome proteins of E. coli with respect to the number of proteins involved and the affinities of their physical interactions: the PriA:PriB interaction is weak in E. coli, but strong in N. gonorrhoeae, and the PriB:DNA interaction is strong in E. coli, but weak in N. gonorrhoeae. In this study, we investigated the functional consequences of this affinity reversal.
We report that N. gonorrhoeae PriA's DNA binding and unwinding activities are similar to those of E. coli PriA, and N. gonorrhoeae PriA's helicase activity is stimulated by its cognate PriB, as it is in E. coli. This finding is significant because N. gonorrhoeae PriB's single-stranded DNA binding activity is weak relative to that of E. coli PriB, and in E. coli, PriB's single-stranded DNA binding activity is important for PriB stimulation of PriA helicase. Furthermore, a N. gonorrhoeae PriB variant defective for binding single-stranded DNA can stimulate PriA's helicase activity, suggesting that DNA binding by PriB might not be important for PriB stimulation of PriA helicase in N. gonorrhoeae. We also demonstrate that N. gonorrhoeae PriB stimulates ATP hydrolysis catalyzed by its cognate PriA. This activity of PriB has not been observed in E. coli, and could be important for PriB stimulation of PriA helicase in N. gonorrhoeae.
The results of this study demonstrate that a bacterial PriB homolog with weak single-stranded DNA binding activity can stimulate the DNA unwinding activity of its cognate PriA helicase. While it remains unclear if N. gonorrhoeae PriB's weak DNA binding activity is required for PriB stimulation of PriA helicase, the ability of PriB to stimulate PriA-catalyzed ATP hydrolysis could play an important role. Thus, the weak interaction between N. gonorrhoeae PriB and DNA might be compensated for by the strong interaction between PriB and PriA, which could result in allosteric activation of PriA's ATPase activity.
PMCID: PMC3179954  PMID: 21861872
17.  Neisseria gonorrhoeae non-susceptible to cephalosporins and quinolones in Northwest Ethiopia 
BMC Infectious Diseases  2013;13:415.
The occurrence of antibiotic resistant Neisseria gonorrhoeae isolates is a serious public health problem in different corners of the globe. The objective of this study was to analyze the antimicrobial susceptibility pattern of N. gonorrhoeae in Northwest Ethiopia.
This was a retrospective study of N. gonorrhoeae isolated from genital swabs of patients referred to the Amhara Regional Health Research Laboratory between September 2006 and June 2012 in Bahir Dar, Ethiopia. A structured check list was used to collect socio-demographic and laboratory variables. Data were analyzed using SPSS software version 16.
Out of 352 genital specimens processed, 29 clinical strains of N. gonorrhoeae were identified. The percentage of N. gonorrhoeae isolates non-susceptible to ceftriaxone, ciprofloxacin, tetracycline and penicillin G was 27.8%, 40.9%, 92.6% and 94.4% respectively. Twenty percent of the isolates were found to be non-susceptible to both ceftriaxone and ciprofloxacin. Non-susceptibility to an injectable cephalosporin and any two of quinolones, penicillins or tetracyclines was observed in 27.8% of the isolates. The percentage of N. gonorrhoeae which were non-susceptible to tetracycline or penicillin G was high throughout the study period. However, the percentage of fluoroquinolone or cephalosporine non-susceptible strains showed an increasing trend.
A high percentage of N. gonorrhoeae isolated from genital specimens in Northwest Ethiopia are non-susceptible to an injectable cephalosporin and any two of quinolones, penicillins or tetracyclines. Treatment of gonorrhea in the study area needs to be guided by antibiotic susceptibility testing of isolates.
PMCID: PMC3844457  PMID: 24007340
Non-susceptible; Neisseria gonorrhoeae; Ethiopia
18.  A Report on the Evaluation of Exhibits—Mediscope 1961 
Thirty-two educational exhibits presented by the Ontario Medical Association at the 1961 Canadian National Exhibition in Toronto in the exhibit known as “Mediscope 1961” were subjected to an evaluative study. Applying the criteria of educational effectiveness to each exhibit, relative ratings for each exhibit as well as the educational value of Mediscope as a whole were obtained. Quantitative data indicated that this venture in health education was a highly successful endeavour, as 80% of the criteria for educational effectiveness were met by all exhibits. In addition, the study emphasized the potential of educational exhibits in the field of public health education as well as education of specific groups.
The desirability of similar studies is stressed. In addition to quantitative assessment of educational exhibits, such studies would disclose the impact of health information on the attitudes and behavioural changes on the part of the public.
PMCID: PMC1920905  PMID: 20327352
19.  Mortality from Parkinson's disease and other causes among a workforce manufacturing paraquat: a retrospective cohort study 
BMJ Open  2011;1(2):e000283.
To assess the risk of Parkinson's disease (PD) and update information on mortality from major causes of death among a UK workforce who manufactured paraquat (PQ) between 1961 and 1995. There have been no previous studies of the incidence of PD among PQ production workers, although much epidemiological literature exists concerning the relationship between pesticides and PD, and interest has focused on PQ and its users.
The cohort included all employees who had ever worked on any of the four plants at Widnes where PQ was manufactured between 1961 and 1995, and 926 male and 42 female workers were followed through 30 June 2009. Mortalities for males were compared with national and local rates, including rates for PD as a mentioned cause of death.
Overall, 307 workers had died by 30 June 2009. One male death was due to PD, and no other death certificate mentioned PD. At least 3.3 death certificates of male employees would have been expected to have mentioned PD (standardised mortality ratio=31; 95% CI 1 to 171). Personal monitoring results were indicative that the exposure of a PQ production worker on a daily basis was at least comparable with that of a PQ sprayer or mixer/loader. Reduced mortalities compared with local rates were found for major causes of death.
The study provided no evidence of an increased risk of PD, or increased mortalities from other causes.
Article summary
Article focus
Many epidemiological studies have been conducted to investigate the relationship between exposure to pesticides and Parkinson's disease (PD) since a report that the toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused acute parkinsonism in a small group of drug addicts, and several have focused on paraquat (PQ) in part because of its structural similarity to a toxic metabolite of MPTP.
Case–control studies provide much of the information about a possible association between PD and exposure to PQ, but most have small numbers of subjects exposed to PQ and/or limited exposure information.
This study is the first investigation of mortality from PD among a cohort of PQ manufacturing workers.
Key messages
The study provided no evidence of increased mortalities from major causes of death. There was no evidence of increased mortality (underlying and mentioned cause) from PD.
Personal monitoring results indicated that workers engaged in PQ production were likely to have had a higher exposure to PQ than many of the subjects in case–control studies classified as exposed to PQ.
Strengths and limitations of this study
A major strength of the study is that it is a cohort study. Exposure of workers to PQ is confirmed by comprehensive job histories and the availability of personal monitoring information.
Limitations of the study include its size and power, although the upper confidence limit of the standardised mortality ratio for mentions of PD is relatively low (171). In addition, only information from death certificates of deceased workers was available, and it was not possible to study the morbidity of the entire group.
PMCID: PMC3211049  PMID: 22080539
20.  The Neisseria Lipooligosaccharide-Specific α-2,3-Sialyltransferase Is a Surface-Exposed Outer Membrane Protein  
Infection and Immunity  2002;70(7):3744-3751.
Neisseria gonorrhoeae and Neisseria meningitidis express an ∼43-kDa α-2,3-sialyltransferase (Lst) that sialylates the surface lipooligosaccharide (LOS) by using exogenous (in all N. gonorrhoeae strains and some N. meningitidis serogroups) or endogenous (in other N. meningitidis serogroups) sources of 5′-cytidinemonophospho-N-acetylneuraminic acid (CMP-NANA). Sialylation of LOS can protect N. gonorrhoeae and N. meningitidis from complement-mediated serum killing and from phagocytic killing by neutrophils. The precise subcellular location of Lst has not been determined. We confirm and extend previous studies by demonstrating that Lst is located in the outer membrane and is surface exposed in both N. gonorrhoeae and N. meningitidis. Western immunoblot analysis of subcellular fractions of N. gonorrhoeae strain F62 and N. meningitidis strain MC58⊄3 (an acapsulate serogroup B strain) performed with rabbit antiserum raised against recombinant Lst revealed an ∼43-kDa protein exclusively in outer membrane preparations of both pathogens. Inner membrane, periplasmic, cytoplasmic, and culture supernatant fractions were devoid of Lst, as determined by Western blot analysis. Consistent with this finding, outer membrane fractions of N. gonorrhoeae were significantly enriched for sialyltransferase enzymatic activity. A trace of enzymatic activity was detected in inner membrane fractions, which may have represented Lst in transit to the outer membrane or may have represented inner membrane contamination of outer membrane preparations. Subcellular preparations of an isogenic lst insertion knockout mutant of N. gonorrhoeae F62 (strain ST01) expressed neither a 43-kDa immunoreactive protein nor sialyltransferase activity. Anti-Lst rabbit antiserum bound to whole cells of N. meningitidis MC58⊄3 and wild-type N. gonorrhoeae F62 but not to the Lst mutant ST01, indicating the surface exposure of the enzyme. Although the anti-Lst antiserum avidly bound enzymatically active, recombinant Lst, it inhibited Lst (sialyltransferase) activity by only about 50% at the highest concentration of antibody used. On the contrary, anti-Lst antiserum did not inhibit sialylation of whole N. gonorrhoeae cells in the presence of exogenous CMP-NANA, suggesting that the antibody did not bind to or could not access the enzyme active site on the surface of viable Neisseria cells. Taken together, these results indicate that Lst is an outer membrane, surface-exposed glycosyltransferase. To our knowledge, this is the first demonstration of the localization of a bacterial glycosyltransferase to the outer membrane of gram-negative bacteria.
PMCID: PMC128106  PMID: 12065517
21.  Binding of Progesterone to Neisseria gonorrhoeae and Other Gram-Negative Bacteria 
Infection and Immunity  1977;16(1):115-123.
The binding of [1,2-3H]progesterone to progesterone-sensitive Neisseria gonorrhoeae CS-7 and the progesterone-insensitive Neisseria mucosa, Pseudomonas aeruginosa, and Salmonella typhimurium (rough and smooth strains) was investigated. The kinetics of binding to N. gonorrhoeae CS-7 demonstrated that the majority of the progesterone binding occurred and equilibrium was reached within the first 30 min. Despite the rapid binding of progesterone, only about 20% of the added steroid was bound at the cell concentration used throughout this study. Whole cells of progesterone-insensitive bacteria bound progesterone less efficiently than the progesterone-sensitive N. gonorrhoeae CS-7. N. mucosa bound low amounts of this steroid (20% of that bound by N. gonorrhoeae CS-7) whereas the other gram-negative bacteria exhibited little progesterone binding (<3% of that bound by N. gonorrhoeae CS-7). The outer membrane permeability of N. gonorrhoeae CS-7, as measured by crystal violet uptake and inhibition, was similar to the deep rough mutant of S. typhimurium TA 1535. The latter organism neither bound nor was inhibited by progesterone. However, isolated cell envelopes of N. gonorrhoeae and progesterone-insensitive bacteria all bound progesterone equally well. Cortisone and cholesterol, althouh structurally similar to progesterone, were not inhibitory to N. gonorrhoeae and did not bind to whole cells as well as progesterone. The major site of progesterone binding appeared to be the cytoplasmic membrane, which bound four times more progesterone than the outer membrane. In addition, isolated cytoplasmic membrane proteins bound more than three times more progesterone per milligram of protein than the intact membrane.
PMCID: PMC421497  PMID: 406199
22.  Gonorrhoea in inner London: results of a cross sectional study. 
BMJ : British Medical Journal  1997;314(7096):1719-1723.
OBJECTIVES: To estimate population based incidence rates of gonorrhoea in an inner London area and examine relations with age, ethnic group, and socioeconomic deprivation. DESIGN: Cross sectional study. SETTING: 11 departments of genitourinary medicine in south and central London. SUBJECTS: 1978 first episodes of gonorrhoea diagnosed in 1994 and 1995 in residents of 73 electoral wards in the boroughs of Lambeth, Southwark, and Lewisham who attended any of the departments of genitourinary medicine. MAIN OUTCOME MEASURES: Yearly age, sex, and ethnic group specific rates of gonorrhoea per 100,000 population aged 15-59 years; rate ratios for the effects of age and ethnic group on gonorrhoea rates in women and men before and after adjustment for confounding factors. RESULTS: Overall incidence rates of gonorrhoea in residents of Lambeth, Southwark, and Lewisham were 138.3 cases yearly per 100,000 women and 291.9 cases yearly per 100,000 men aged 15-59 years. At all ages gonorrhoea rates were higher in non-white minority ethnic groups. Rate ratios for the effect of age adjusted for ethnic group and underprivilege were 15.2 (95% confidence interval 11.6 to 19.7) for women and 2.0 (1.7 to 2.5) for men aged 15-19 years compared with those over 30. After deprivation score and age were taken into account, women from black minority groups were 10.5 (8.6 to 12.8) times as likely and men 11.0 (9.7 to 12.6) times as likely as white people to experience gonorrhoea. CONCLUSIONS: Gonorrhoea rates in Lambeth, Southwark, and Lewisham in 1994-5 were six to seven times higher than for England and Wales one year earlier. The presentation of national trends thus hides the disproportionate contribution of ongoing endemic transmission in the study area. Teenage women and young adult men, particularly those from black minority ethnic groups, are the most heavily affected, even when socioeconomic underprivilege is taken into account. There is urgent need for resources for culturally appropriate research and effective intervention to prevent gonococcal infections and their long term sequelae in this population.
PMCID: PMC2126883  PMID: 9185497
23.  Risk factors for gonorrhoea: case-control study. 
Genitourinary Medicine  1997;73(6):518-521.
OBJECTIVE: To define risk factors for gonococcal infection. METHODS: A case-control study comparing 200 gonorrhoea cases with 400 patients with non-gonococcal genitourinary infections and 400 patients with various skin diseases, all of them attending City Department for Skin and Venereal Diseases In Belgrade (Yugoslavia) from October 1993 to December 1994. RESULTS: According to multivariate logistic regression analysis the following factors were significantly related to gonorrhoea in men: education level, sexual contact same day as meeting, condom use, history of prior gonorrhoea, and casual and/or new sex partner in the past month. Age, sexual contact same day as meeting, number of partners in the past year, and frequency of sexual intercourse in the past month were independently, significantly related to gonorrhoea in women. Also, in females, gonorrhoea was significantly more frequent in industrial workers and supported people. CONCLUSION: Since sexual behaviour, low education level, younger ages, and low socioeconomic status were found to be related to gonococcal infection, health education at early age seems to be the most appropriate means of altering high risk behaviour.
PMCID: PMC1195937  PMID: 9582473
24.  Neisseria gonorrhoeae isolated at St. Mary's Hospital London, 1980-91. 
Genitourinary Medicine  1993;69(4):286-289.
OBJECTIVE--To describe and discuss the trends in the isolation of Neisseria gonorrhoeae from patients attending the Genitourinary Medicine Clinic at St. Mary's Hospital, Paddington, London between 1980 and 1991. DESIGN--A retrospective study of the total number of gonococci isolated over an eleven year period was performed. In addition, for the years 1988-1991 the number of isolates from homosexual men was analysed by age of the patient, site of infection and HIV antibody status of the patient. RESULTS--The total number of N. gonorrhoeae isolates identified declined markedly between 1980 and 1989 from 3670 to 750 isolates. Over the same time period the number of specimens screened for N. gonorrhoeae fell by 50%. In 1990 there was an increase in N. gonorrhoeae isolates but this was not maintained, and in 1991 the number of N. gonorrhoeae fell to its lowest level of 638 isolates. The decrease since 1980 occurred in both men and women although the number of rectal isolates from men showed a steeper decline reaching its lowest level of 24 isolates in 1988. The number of rectal isolates from homosexual men has since increased with a peak in 1990. Many of the infections among homosexual men occurred in older men and included insignificant number of patients who were HIV positive. CONCLUSION--Gonorrhoea among attenders at St. Mary's Hospital has declined dramatically since 1980 following trends reported from much of Europe. The increase in gonococcal isolates since 1989 and the peak in 1990 are unexplained but are coincident with a higher number of isolates from homosexual men.
PMCID: PMC1195089  PMID: 7721290
25.  A serovar analysis of heterosexual gonorrhoea in Edinburgh 1986-90. 
Genitourinary Medicine  1992;68(1):16-19.
OBJECTIVE--To analyse the frequency of different gonococcal serovars within Edinburgh, Scotland and to describe changes that occurred in the frequency of such serovars over time. METHODS--All heterosexual patients with a diagnosis of gonorrhoea confirmed on culture between January 1986 and December 1990 had their gonococcal strain serotyped. Temporal changes in the prevalence of gonorrhoea and the serovar of the isolates were analysed. RESULTS--Isolates of Neisseria gonorrhoeae from 1356 episodes of gonorrhoea were serotyped. Three serovars, Bajk (IB-3/IB-6), Bacejk (IB-1/IB-2) and Aedgkih (IA-1/IA-2), dominated, occurring in two-thirds of all infections. Over the study period Bajk (IB-3/IB-6) and Aedgkih (IA-1/IA-2) isolates declined in frequency in parallel with an overall fall in the prevalence of gonorrhoea but Bacejk (IB-1/IB-2) persisted at a lower but fairly constant level. Despite a fall in the number of gonococcal infections the variety of new serovars being isolated fluctuated. CONCLUSIONS--The ability of some serovars to persist while others decline in incidence may be partially related to antibiotic sensitivities but other factors such as an ability to evade the immune response and transfer of serovars from one population group to another may also be important.
PMCID: PMC1194791  PMID: 1548006

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