Kooperativer Bibliotheksverbund

Berlin Brandenburg

and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • 2014  (15)
Type of Medium
Language
Year
  • 2014  (15)
  • 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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    In: Health Physics, 2014, Vol.106(1), pp.21-38
    Description: ABSTRACT: In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24 h post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg of either PEG-G-CSF affected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9 mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle-treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation.
    Keywords: Polyethylene Glycol ; Rodents ; Bone Marrow ; Health Physics ; Radiation ; Survival Analysis;
    ISSN: 0017-9078
    E-ISSN: 15385159
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    In: Health Physics, 2014, Vol.106(1), pp.48-55
    Description: ABSTRACT: Approval of radiation countermeasures through the FDA Animal Rule requires pivotal efficacy screening in one or more species that are expected to react with a response similar to humans (21 C.F.R. § 314.610, drugs; § 601.91, biologics). Animal models used in screening studies should reflect the dose response relationship (DRR), clinical presentation, and pathogenesis of lung injury in humans. Over the past 5 y, the authors have characterized systematically the temporal onset, dose-response relationship (DRR), and pathologic outcomes associated with acute, high dose radiation exposure in three diverse mouse strains. In these studies, C57L/J, CBA/J, and C57BL/6J mice received wide field irradiation to the whole thorax with shielding of the head, abdomen, and forelimbs. Doses were delivered at a rate of 69 cGy min using an x-ray source operated at 320 kVp with half-value layer (HVL) of 1 mm Cu. For all strains, radiation dose was associated significantly with 180 d mortality (p 〈 0.0001). The lethal dose for 50% of animals within the first 180 d (LD50/180) was 11.35 Gy (95% CI 11.1–11.6 Gy) for C57L/J mice, 14.17 Gy (95% CI 13.9–14.5 Gy) for CBA/J mice, and 14.10 Gy (95% CI 12.2–16.4 Gy) for C57BL/6J mice. The LD50/180 in the C57L/J strain was most closely analogous to the DRR for clinical incidence of pneumonitis in non-human primates (10.28 Gy; 95% CI 9.9–10.7 Gy) and humans (10.60 Gy; 95% CI 9.9–12.1 Gy). Furthermore, in the C57L/J strain, there was no gender-specific difference in DRR (p = 0.5578). The reliability of the murine models is demonstrated by the reproducibility of the dose-response and consistency of disease presentation across studies.Health Phys. 106(1):000-000; 2014
    Keywords: Lungs ; Injuries ; Radiation ; Rodents ; Pathogenesis ; Health Physics;
    ISSN: 0017-9078
    E-ISSN: 15385159
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    In: Health Physics, 2014, Vol.106(1), pp.39-47
    Description: ABSTRACT: The identification of the optimal administration schedule for an effective medical countermeasure is critical for the effective treatment of individuals exposed to potentially lethal doses of radiation. The efficacy of filgrastim (Neupogen®), a potential medical countermeasure, to improve survival when initiated at 48 h following total body irradiation in a non-human primate model of the hematopoietic syndrome of the acute radiation syndrome was investigated. Animals were exposed to total body irradiation, antero-posterior exposure, total midline tissue dose of 7.5 Gy, (target lethal dose 50/60) delivered at 0.80 Gy min, using linear accelerator-derived 6 MV photons. All animals were administered medical management. Following irradiation on day 0, filgrastim (10 μg kg d) or the control (5% dextrose in water) was administered subcutaneously daily through effect (absolute neutrophil count ≥ 1,000 cells μL for three consecutive days). The study (n = 80) was powered to demonstrate a 25% improvement in survival following the administration of filgrastim or control beginning at 48 ± 4 h post-irradiation. Survival analysis was conducted on the intention-to-treat population using a two-tailed null hypothesis at a 5% significance level. Filgrastim, initiated 48 h after irradiation, did not improve survival (2.5% increase, p = 0.8230). These data demonstrate that efficacy of a countermeasure to mitigate lethality in the hematopoietic syndrome of the acute radiation syndrome can be dependent on the interval between irradiation and administration of the medical countermeasure.
    Keywords: Glycoproteins ; Mortality ; Radiation ; Health Physics ; Survival Analysis;
    ISSN: 0017-9078
    E-ISSN: 15385159
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: mBio, 11 February 2014, Vol.5(1), pp.e01081-13
    Description: To adapt to stresses encountered in stationary phase, Gram-negative bacteria utilize the alternative sigma factor RpoS. However, some species lack RpoS; thus, it is unclear how stationary-phase adaptation is regulated in these organisms. Here we defined the growth-phase-dependent transcriptomes of Haemophilus ducreyi, which lacks an RpoS homolog. Compared to mid-log-phase organisms, cells harvested from the stationary phase upregulated genes encoding several virulence determinants and a homolog of hfq. Insertional inactivation of hfq altered the expression of ~16% of the H. ducreyi genes. Importantly, there were a significant overlap and an inverse correlation in the transcript levels of genes differentially expressed in the hfq inactivation mutant relative to its parent and the genes differentially expressed in stationary phase relative to mid-log phase in the parent. Inactivation of hfq downregulated genes in the flp-tad and lspB-lspA2 operons, which encode several virulence determinants. To comply with FDA guidelines for human inoculation experiments, an unmarked hfq deletion mutant was constructed and was fully attenuated for virulence in humans. Inactivation or deletion of hfq downregulated Flp1 and impaired the ability of H. ducreyi to form microcolonies, downregulated DsrA and rendered H. ducreyi serum susceptible, and downregulated LspB and LspA2, which allow H. ducreyi to resist phagocytosis. We propose that, in the absence of an RpoS homolog, Hfq serves as a major contributor of H. ducreyi stationary-phase and virulence gene regulation. The contribution of Hfq to stationary-phase gene regulation may have broad implications for other organisms that lack an RpoS homolog. Pathogenic bacteria encounter a wide range of stresses in their hosts, including nutrient limitation; the ability to sense and respond to such stresses is crucial for bacterial pathogens to successfully establish an infection. Gram-negative bacteria frequently utilize the alternative sigma factor RpoS to adapt to stresses and stationary phase. However, homologs of RpoS are absent in some bacterial pathogens, including Haemophilus ducreyi, which causes chancroid and facilitates the acquisition and transmission of HIV-1. Here, we provide evidence that, in the absence of an RpoS homolog, Hfq serves as a major contributor of stationary-phase gene regulation and that Hfq is required for H. ducreyi to infect humans. To our knowledge, this is the first study describing Hfq as a major contributor of stationary-phase gene regulation in bacteria and the requirement of Hfq for the virulence of a bacterial pathogen in humans.
    Keywords: Gene Expression Regulation, Bacterial ; Haemophilus Ducreyi -- Genetics ; Host Factor 1 Protein -- Metabolism ; Virulence Factors -- Biosynthesis
    E-ISSN: 2150-7511
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    In: Health Physics, 2014, Vol.106(1), pp.7-20
    Description: ABSTRACT: Hematopoietic growth factors (HGF) are recommended therapy for high dose radiation exposure, but unfavorable administration schedules requiring early and repeat dosing limit the logistical ease with which they can be used. In this report, using a previously described murine model of H-ARS, survival efficacy and effect on hematopoietic recovery of unique PEGylated HGF were investigated. The PEGylated-HGFs possess longer half-lives and more potent hematopoietic properties than corresponding non-PEGylated-HGFs. C57BL/6 mice underwent single dose lethal irradiation (7.76–8.72 Gy, Cs, 0.62–1.02 Gy min) and were treated with various dosing regimens of 0.1, 0.3, and 1.0 mg kg of analogs of human PEG-G-CSF, murine PEG-GM-CSF, or human PEG-IL-11. Mice were administered one of the HGF analogs at 24–28 h post irradiation, and in some studies, additional doses given every other day (beginning with the 24–28 h dose) for a total of three or nine doses. Thirty-day (30 d) survival was significantly increased with only one dose of 0.3 mg kg of PEG-G-CSF and PEG-IL-11 or three doses of 0.3 mg kg of PEG-GM-CSF (p ≤ 0.006). Enhanced survival correlated with consistently and significantly enhanced WBC, NE, RBC, and PLT recovery for PEG-G- and PEG-GM-CSF, and enhanced RBC and PLT recovery for PEG-IL-11 (p ≤ 0.05). Longer administration schedules or higher doses did not provide a significant additional survival benefit over the shorter, lower dose, schedules. These data demonstrate the efficacy of BBT’s PEG-HGF to provide significantly increased survival with fewer injections and lower drug doses, which may have significant economic and logistical value in the aftermath of a radiation event.
    Keywords: Glycoproteins ; Cells ; Rodents ; Radiation ; Health Physics;
    ISSN: 0017-9078
    E-ISSN: 15385159
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Description: Multiple-outcome longitudinal data are abundant in clinical investigations. For example, infections with different pathogenic organisms are often tested concurrently, and assessments are usually taken repeatedly over time. It is therefore natural to consider a multivariate modeling approach to accommodate the underlying interrelationship among the multiple longitudinally measured outcomes. This dissertation proposes a multivariate semiparametric modeling framework for such data. Relevant estimation and inference procedures as well as model selection tools are discussed within this modeling framework. The first part of this research focuses on the analytical issues concerning binary data. The second part extends the binary model to a more general situation for data from the exponential family of distributions. The proposed model accounts for the correlations across the outcomes as well as the temporal dependency among the repeated measures of each outcome within an individual. An important feature of the proposed model is the addition of a bivariate smooth function for the depiction of concurrent nonlinear and possibly interacting influences of two independent variables on each outcome. For model implementation, a general approach for parameter estimation is developed by using the maximum penalized likelihood method. For statistical inference, a likelihood-based resampling procedure is proposed to compare the bivariate nonlinear effect surfaces across the outcomes. The final part of the dissertation presents a variable selection tool to facilitate model development in practical data analysis. Using the adaptive least absolute shrinkage and selection operator (LASSO) penalty, the variable selection tool simultaneously identifies important fixed effects and random effects, determines the correlation structure of the outcomes, and selects the interaction effects in the bivariate smooth functions. Model selection and estimation are performed through a two-stage procedure based on an expectation-maximization (EM) algorithm. Simulation studies are conducted to evaluate the performance of the proposed methods. The utility of the methods is demonstrated through several clinical applications.
    Keywords: Biostatistics ; Regression Analysis -- Data Processing -- Research -- Methodology ; Mathematical Statistics -- Longitudinal Studies -- Research ; Multivariate Analysis -- Research -- Methodology ; Estimation Theory -- Research ; Biometry -- Methodology -- Research ; Clinical Trials -- Statistical Methods -- Research ; Expectation-Maximization Algorithms -- Research ; Binary System (Mathematics) -- Research ; Nonparametric Statistics -- Research ; Probabilities -- Data Processing ; Real-Time Data Processing -- Research ; Parameter Estimation -- Research ; Latent Variables -- Research ; Meta-Analysis -- Research -- Methodology ; Stochastic Processes -- Research ; Least Squares -- Research
    Source: Networked Digital Library of Theses and Dissertations
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: Marine and Petroleum Geology, 2014, Vol.56, p.255(11)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.marpetgeo.2014.02.013 Byline: Barry Katz, Fang Lin Abstract: There has been a revival in hydrocarbon source rock characterization and development associated with growing interest in unconventional resources, where these fine-grained organic-rich rocks act as both source and reservoir. To-date, the exploration focus on shale reservoirs has been largely on marine systems. Lacustrine source rocks for conventional resources are geographically important, dominating regions such as China, Indonesia, and Brazil's resource-base. However, they have been generally untested for unconventional resources. There are a number of key differences in the nature of these hydrocarbon systems that should be considered when assessing whether lacustrine systems may represent future unconventional opportunities in areas where the conventional resource-base is dominated by lacustrine-sourced oil. Among the key differences between these depositional systems is the greater sensitivity to high frequency climatic variability within lacustrine systems. Lacustrine systems are highly sensitive to changes in the balance between precipitation and evaporation, which may lead to rapid changes in lake level, potentially exceeding 600 m. These changes in depositional conditions are geologically rapid and may occur over periods of thousands of years. Such changes can reduce the areal extent of potentially thick source rock intervals to only those portions of a basin where a permanent deep lake was present. Thus the core unconventional target area may be geographically limited compared with their marine counterpart. Although potentially areally limited, a review of many lacustrine source rocks suggests that their thicknesses are often significantly greater than marine source rocks. An examination of the more distal portions of lacustrine systems, where better source rock potential is present reveals that there is generally limited connectivity between source and conventional reservoir. In these settings, such as the Wind River basin (Waltman Shale), the hydrocarbons remain trapped within the shales, potentially leading to over-pressured hydrocarbon charged systems. Such conditions suggest that although areally limited, viable unconventional targets may exist, if suitable reservoir conditions are present. Finally, the character of the oils produced is different in these settings, with lacustrine oils being waxy and displaying different hydrocarbon generation and cracking kinetics. High wax oils display distinct flow characteristics, being more viscous, and may offer different production challenges than their non-waxy marine equivalents. Additionally, differences in their cracking kinetics may indicate that the timing of gas generation for shale gas plays may differ significantly from marine systems. Author Affiliation: Chevron Energy Technology Company (ETC), Houston, TX 77379, USA Article History: Received 29 October 2013; Revised 16 February 2014; Accepted 20 February 2014
    Keywords: Rain ; Shale Oils
    ISSN: 0264-8172
    Source: Cengage Learning, Inc.
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages