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  • 1
    Language: English
    In: BMC microbiology, 24 June 2014, Vol.14, pp.166
    Description: Bacterial lipoproteins often play important roles in pathogenesis and can stimulate protective immune responses. Such lipoproteins are viable vaccine candidates. Haemophilus ducreyi, which causes the sexually transmitted disease chancroid, expresses a number of lipoproteins during human infection. One such lipoprotein, OmpP4, is homologous to the outer membrane lipoprotein e (P4) of H. influenzae. In H. influenzae, e (P4) stimulates production of bactericidal and protective antibodies and contributes to pathogenesis by facilitating acquisition of the essential nutrients heme and nicotinamide adenine dinucleotide (NAD). Here, we tested the hypothesis that, like its homolog, H. ducreyi OmpP4 contributes to virulence and stimulates production of bactericidal antibodies. We determined that OmpP4 is broadly conserved among clinical isolates of H. ducreyi. We next constructed and characterized an isogenic ompP4 mutant, designated 35000HPompP4, in H. ducreyi strain 35000HP. To test whether OmpP4 was necessary for virulence in humans, eight healthy adults were experimentally infected. Each subject was inoculated with a fixed dose of 35000HP on one arm and three doses of 35000HPompP4 on the other arm. The overall parent and mutant pustule formation rates were 52.4% and 47.6%, respectively (P = 0.74). These results indicate that expression of OmpP4 in not necessary for H. ducreyi to initiate disease or progress to pustule formation in humans. Hyperimmune mouse serum raised against purified, recombinant OmpP4 did not promote bactericidal killing of 35000HP or phagocytosis by J774A.1 mouse macrophages in serum bactericidal and phagocytosis assays, respectively. Our data suggest that, unlike e (P4), H. ducreyi OmpP4 is not a suitable vaccine candidate. OmpP4 may be dispensable for virulence because of redundant mechanisms in H. ducreyi for heme acquisition and NAD utilization.
    Keywords: Bacterial Outer Membrane Proteins -- Metabolism ; Chancroid -- Microbiology ; Haemophilus Ducreyi -- Pathogenicity ; Virulence Factors -- Metabolism
    E-ISSN: 1471-2180
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  • 2
    Language: English
    In: BMC medicine, 06 November 2014, Vol.12, pp.204
    Description: Nearly 1 in 5 people living with HIV in the United States are unaware they are infected. Therefore, it is important to develop and evaluate health communication messages that clinicians can use to encourage HIV testing. The objective was to evaluate health communication messages designed to increase HIV testing rates among women and evaluate possible moderators of message effect. We used a randomized four-arm clinical trial conducted at urban community outpatient health clinics involving 1,919 female patients, 18 to 64 years old. The four health message intervention groups were: i) information-only control; ii) one-sided message describing the advantages of HIV testing; iii) two-sided message acknowledging a superficial objection to testing (i.e., a 20 minute wait for results) followed by a description of the advantages of testing; and iv) two-sided message acknowledging a serious objection (i.e., fear of testing positive for HIV) followed by a description of the advantages of testing. The main outcome was acceptance of an oral rapid HIV test. Participants were randomized to receive the control message (n = 483), one-sided message (n = 480), two-sided message with a superficial objection (n = 481), or two-sided message with a serious objection (n = 475). The overall rate of HIV test acceptance was 83%. The two-sided message groups were not significantly different from the controls. The one-sided message group, however, had a lower rate of testing (80%) than the controls (86%) (OR, 0.66; 95% CI, 0.47-0.93; P = 0.018). "Perceived obstacles to HIV testing" moderated this effect, indicating that the decrease in HIV test acceptance for the one-sided message group was only statistically significant for those who had reported high levels of obstacles to HIV testing (OR, 0.36; 95% CI, 0.19-0.67; P = 0.001). None of the messages increased test acceptance. The one-sided message decreased acceptance and this effect was particularly true for women with greater perceived obstacles to testing, the very group one would most want to persuade. This finding suggests that efforts to persuade those who are reluctant to get tested, in some circumstances, may have unanticipated negative effects. Other approaches to messaging around HIV testing should be investigated, particularly with diverse, behaviorally high-risk populations. Clinicaltrials.gov Identifier: NCT00771537. Registration date: October 10. 2008.
    Keywords: HIV Infections -- Diagnosis ; Mass Screening -- Statistics & Numerical Data ; Patient Acceptance of Health Care -- Statistics & Numerical Data ; Patient Education As Topic -- Methods
    E-ISSN: 1741-7015
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  • 3
    Language: English
    In: The Journal of infectious diseases, 15 June 2011, Vol.203(12), pp.1859-65
    Description: Haemophilus ducreyi 35000HP contains a homolog of the CpxRA 2-component signal transduction system, which controls the cell envelope stress response system in other gram-negative bacteria and regulates some important H. ducreyi virulence factors. A H. ducreyi cpxR mutant was compared with its parent for virulence in the human challenge model of experimental chancroid. The pustule formation rate in 5 volunteers was 33% (95% confidence interval [CI], 1.3%-65.3%) at 15 parent sites and 40% (95% CI, 18.1%-61.9%) at 15 mutant sites (P = .35). Thus, the cpxR mutant was not attenuated for virulence. Inactivation of the H. ducreyi cpxR gene did not reduce the ability of this mutant to express certain proven virulence factors, including the DsrA serum resistance protein and the LspA2 protein, which inhibits phagocytosis. These results expand our understanding of the involvement of the CpxRA system in regulating virulence expression in H. ducreyi.
    Keywords: Bacterial Proteins -- Genetics ; Chancroid -- Microbiology ; Haemophilus Ducreyi -- Genetics
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 4
    Language: English
    In: The Journal of infectious diseases, November 2012, Vol.206(9), pp.1407-14
    Description: Haemophilus ducreyi encounters several classes of antimicrobial peptides (APs) in vivo and utilizes the sensitive-to-antimicrobial-peptides (Sap) transporter as one mechanism of AP resistance. A mutant lacking the periplasmic solute-binding component, SapA, was somewhat more sensitive to the cathelicidin LL-37 than the parent strain and was partially attenuated for virulence. The partial attenuation led us to question whether the transporter is fully abrogated in the sapA mutant. We generated a nonpolar sapBC mutant, which lacks both inner membrane permeases of the Sap transporter, and tested the mutant for virulence in human volunteers. In vitro, we compared LL-37 resistance phenotypes of the sapBC and sapA mutants. Unlike the sapA mutant, the sapBC mutant was fully attenuated for virulence in human volunteers. In vitro, the sapBC mutant exhibited significantly greater sensitivity than the sapA mutant to killing by LL-37. Similar to the sapA mutant, the sapBC mutant did not affect H. ducreyi's resistance to human defensins. Compared with the sapA mutant, the sapBC mutant exhibited greater attenuation in vivo, which directly correlated with increased sensitivity to LL-37 in vitro. These results strongly suggest that the SapBC channel retains activity when SapA is removed.
    Keywords: Drug Resistance, Bacterial ; Antimicrobial Cationic Peptides -- Pharmacology ; Haemophilus Ducreyi -- Enzymology ; Membrane Transport Proteins -- Metabolism ; Virulence Factors -- Metabolism
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 5
    Language: English
    In: Infection and Immunity, 2012, Vol. 80(2), p.679
    Description: Sialylated glycoconjugates on the surfaces of mammalian cells play important roles in intercellular communication and self-recognition. The sialic acid preferentially expressed in human tissues is N-acetylneuraminic acid (Neu5Ac). In a process called molecular mimicry, many bacterial pathogens decorate their cell surface glycolipids with Neu5Ac. Incorporation of Neu5Ac into bacterial glycolipids promotes bacterial interactions with host cell receptors called Siglecs. These interactions affect bacterial adherence, resistance to serum killing and phagocytosis, and innate immune responses. Haemophilus ducreyi, the etiologic agent of chancroid, expresses lipooligosaccharides (LOS) that are highly sialylated. However, an H. ducreyi sialyltransferase (lst) mutant, whose LOS contain reduced levels of Neu5Ac, is fully virulent in human volunteers. Recently, a second sialyltransferase gene (Hd0053) was discovered in H. ducreyi, raising the possibility that Hd0053 compensated for the loss of lst during human infection. CMP-Neu5Ac is the obligate nucleotide sugar donor for all bacterial sialyltransferases; LOS derived from an H. ducreyi CMP-Neu5Ac synthetase (neuA) mutant has no detectable Neu5Ac. Here, we compared an H. ducreyi neuA mutant to its wild-type parent in several models of pathogenesis. In human inoculation experiments, the neuA mutant formed papules and pustules at rates that were no different than those of its parent. When grown in media with and without Neu5Ac supplementation, the neuA mutant and its parent had similar phenotypes in bactericidal, macrophage uptake, and dendritic cell activation assays. Although we cannot preclude a contribution of LOS sialylation to ulcerative disease, these data strongly suggest that sialylation of LOS is dispensable for H. ducreyi pathogenesis in humans.
    Keywords: Bacterial Proteins -- Metabolism ; Chancroid -- Microbiology ; Haemophilus Ducreyi -- Metabolism ; Lipopolysaccharides -- Metabolism ; N-Acetylneuraminic Acid -- Metabolism;
    ISSN: 1098-5522
    ISSN: 10985522
    ISSN: 00199567
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  • 6
    Language: English
    In: Patient Education and Counseling, October 2012, Vol.89(1), pp.184-190
    Description: To evaluate (PC), a program that employed lay health workers to motivate antiretroviral adherence among persons living with HIV with coverage from Indiana's high-risk insurance pool. Four hundred and forty nine participants living in the greater Indianapolis area were randomly allocated to treatment ( = 91) or control ( = 358) groups and followed for one year. Compared to control subjects, PC subjects were more likely to adhere to HIV medications (medication possession ratio adherence ≥0.95, OR = 1.83, = 0.046), and to achieve undetectable viral load (〈50 copies/mL, OR = 2.01, = 0.011) in the 12 months following introduction of PC. There were no significant differences observed between groups in any of self-reported health status indicators. Estimates suggest that PC clients were 16% more likely to have undetectable viral loads than clients in standard care. The incremental program cost was approximately $10,000 for each additional person who achieved an undetectable viral load. As persons living with HIV experience greater longevity and healthcare reform expands coverage to these high-risk populations, greater demands will be placed on the HIV-care workforce. Results suggest lay health workers may serve as effective adjuncts to professional care providers.
    Keywords: Lay Health Workers ; Medication Adherence ; HIV ; Medicine ; Public Health
    ISSN: 0738-3991
    E-ISSN: 1873-5134
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  • 7
    Language: English
    In: Infection and immunity, September 2010, Vol.78(9), pp.3898-904
    Description: Haemophilus ducreyi must adapt to the environment of the human host to establish and maintain infection in the skin. Bacteria generally utilize stress response systems, such as the CpxRA two-component system, to adapt to hostile environments. CpxRA is the only obvious two-component system contained in the H. ducreyi genome and negatively regulates the lspB-lspA2 operon, which encodes proteins that enable the organism to resist phagocytosis. We constructed an unmarked, in-frame H. ducreyi cpxA deletion mutant, 35000HPDeltacpxA. In human inoculation experiments, 35000HPDeltacpxA formed papules at a rate and size that were significantly less than its parent and was unable to form pustules compared to the parent. CpxA usually has kinase and phosphatase activities for CpxR, and the deletion of CpxA leads to the accumulation of activated CpxR due to the loss of phosphatase activity and the ability of CpxR to accept phosphate groups from other donors. Using a reporter construct, the lspB-lspA2 promoter was downregulated in 35000HPDeltacpxA, confirming that CpxR was activated. Deletion of cpxA downregulated DsrA, the major determinant of serum resistance in the organism, causing the mutant to become serum susceptible. Complementation in trans restored parental phenotypes. 35000HPDeltacpxA is the first H. ducreyi mutant that is impaired in its ability to form both papules and pustules in humans. Since a major function of CpxRA is to control the flow of protein traffic across the periplasm, uncontrolled activation of this system likely causes dysregulated expression of multiple virulence determinants and cripples the ability of the organism to adapt to the host.
    Keywords: Bacterial Proteins -- Physiology ; Haemophilus Ducreyi -- Pathogenicity ; Protein Kinases -- Physiology
    ISSN: 00199567
    E-ISSN: 1098-5522
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  • 8
    Language: English
    In: Infection and immunity, August 2014, Vol.82(8), pp.3492-502
    Description: (p)ppGpp responds to nutrient limitation through a global change in gene regulation patterns to increase survival. The stringent response has been implicated in the virulence of several pathogenic bacterial species. Haemophilus ducreyi, the causative agent of chancroid, has homologs of both relA and spoT, which primarily synthesize and hydrolyze (p)ppGpp in Escherichia coli. We constructed relA and relA spoT deletion mutants to assess the contribution of (p)ppGpp to H. ducreyi pathogenesis. Both the relA single mutant and the relA spoT double mutant failed to synthesize (p)ppGpp, suggesting that relA is the primary synthetase of (p)ppGpp in H. ducreyi. Compared to the parent strain, the double mutant was partially attenuated for pustule formation in human volunteers. The double mutant had several phenotypes that favored attenuation, including increased sensitivity to oxidative stress. The increased sensitivity to oxidative stress could be complemented in trans. However, the double mutant also exhibited phenotypes that favored virulence. When grown to the mid-log phase, the double mutant was significantly more resistant than its parent to being taken up by human macrophages and exhibited increased transcription of lspB, which is involved in resistance to phagocytosis. Additionally, compared to the parent, the double mutant also exhibited prolonged survival in the stationary phase. In E. coli, overexpression of DksA compensates for the loss of (p)ppGpp; the H. ducreyi double mutant expressed higher transcript levels of dksA than the parent strain. These data suggest that the partial attenuation of the double mutant is likely the net result of multiple conflicting phenotypes.
    Keywords: Guanosine Pentaphosphate -- Deficiency ; Haemophilus Ducreyi -- Pathogenicity ; Ligases -- Metabolism ; Pyrophosphatases -- Metabolism
    ISSN: 00199567
    E-ISSN: 1098-5522
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  • 9
    Language: English
    In: The Journal of infectious diseases, 01 June 2009, Vol.199(11), pp.1671-9
    Description: Haemophilus ducreyi causes chancroid, which facilitates transmission of human immunodeficiency virus type 1. To better understand the biology of H. ducreyi, we developed a human inoculation model. In the present article, we describe clinical outcomes for 267 volunteers who were infected with H. ducreyi. There was a relationship between papule formation and estimated delivered dose. The outcome (either pustule formation or resolution) of infected sites for a given subject was not independent; the most important determinants of pustule formation were sex and host effects. When 41 subjects were infected a second time, their outcomes segregated toward their initial outcome, confirming the host effect. Subjects with pustules developed local symptoms that required withdrawal from the study after a mean of 8.6 days. There were 191 volunteers who had tissue biopsy performed, 173 of whom were available for follow-up analysis; 28 (16.2%) of these developed hypertrophic scars, but the model was otherwise safe. Mutant-parent trials confirmed key features in H. ducreyi pathogenesis, and the model has provided an opportunity to study differential human susceptibility to a bacterial infection.
    Keywords: Chancroid -- Microbiology ; Haemophilus Ducreyi -- Pathogenicity
    ISSN: 0022-1899
    E-ISSN: 15376613
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  • 10
    Language: English
    In: Annals of the Rheumatic Diseases, 22 March 2007, Vol.66(3), p.394
    Description: To evaluate the risk factors for early radiographic changes of knee osteoarthritis.
    Keywords: BMI, Body Mass Index ; Gee, Generalised Estimating Equations ; Jsn, Joint Space Narrowing ; Jsw, Joint Space Width ; K&L, Kellgren and Lawrence ; Rct, Randomised Controlled Trial ; Womac, Western Ontario and Mcmaster Universities ; Radiology ; Degenerative Joint Disease ; Musculoskeletal Syndromes ; Osteoarthritis ; Clinical Diagnostic Tests ; Radiology (Diagnostics)
    ISSN: 0003-4967
    ISSN: 00034967
    E-ISSN: 1468-2060
    E-ISSN: 14682060
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