bluuebunny/crossref_metadata_2025_split huggingface dataset:
When to Stress Over Triptans: A Markov Analysis of Cardiovascular Risk in Migraine Treatment
Authors: Orlando Lori A. , Matchar David B. 
Published: June 2004

Background.—Migraines affect 10% of the U.S. population and the episodes are frequently associated with significant disability. Triptans, 5HT1 receptor agonists, can be highly effective in treating pain and reducing disability. However, reports of cardiac events associated with triptan ingestion have led to concerns about its use in the face of possible cardiac disease.Objective.—Should a patient without known cardiovascular disease (CAD) and moderately severe to severe migraines undergo cardiovascular testing prior to the initiation of triptan therapy?Design.—A Markov model of migraine and cardiac disease using DATA 4.0. Three strategies were compared: (1) use triptans without further evaluation (TREAT); (2) test, then treat if negative (TEST); and (3) avoid triptans (NOTRIPTAN). Triptans were prohibited if a cardiac event occurred.Data.—Model inputs were derived from the literature and subjected to sensitivity analyses across all possible values.Time Horizon.—Markov cycle is 1 week.Outcomes.—The primary outcomes of interest were quality‐adjusted life expectancy, in years (QALYs) and the impact of various cardiovascular risk levels on the preferred strategy.Results.—For the base case results were TREAT 19.4 QALYs, TEST 19.2, NOTRIPTAN 19.1. When altering CAD probability: TREAT dominated from 0 to 87%, TEST 87% to 97%, and NOTRIPTAN above 97%. Results were robust during sensitivity analyses.Conclusions.—This analysis suggests that even for individuals with a relatively high risk of CAD it is not beneficial to perform cardiac testing, nor to avoid triptans. The exact level of cardiac risk at which testing should be considered is probably at or above 87%.
Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Contributes to Survival of Primary Epithelial Cells Infected with the Periodontal Pathogen
Porphyromonas gingivalis
Authors: Yilmaz Özlem , Jungas Thomas , Verbeke Philippe , Ojcius David M. 
Published: June 2004

ABSTRACT

Porphyromonas gingivalis
, an important periodontal pathogen, infects primary gingival epithelial cells (GECs). Despite the large number of bacteria that replicate inside the GECs, the host cell remains viable. We demonstrate that
P. gingivalis
triggers rapid and reversible surface phosphatidylserine exposure through a mechanism requiring caspase activation. However, after 1 day of infection, the bacteria no longer induce phosphatidylserine externalization and instead protect infected cells against apoptosis. Infection exerts its effect at the level of mitochondria, as
P. gingivalis
also blocks depolarization of the mitochondrial transmembrane potential and cytochrome
c
release. Interestingly, protein kinase B/Akt is phosphorylated during infection, which can be blocked with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Suppression of the PI3K/Akt pathway following staurosporine treatment results in mitochondrial-membrane depolarization, cytochrome
c
release, DNA fragmentation, and increased apoptosis of infected GECs. Thus,
P. gingivalis
stimulates early surface exposure of phosphatidylserine, which could downmodulate the inflammatory response, while also promoting host cell survival through the PI3K/Akt pathway.
Adaptation of
Campylobacter jejuni
NCTC11168 to High-Level Colonization of the Avian Gastrointestinal Tract
Authors: Jones Michael A. , Marston Kerrie L. , Woodall Claire A. , Maskell Duncan J. , Linton Dennis , Karlyshev Andrey V. , Dorrell Nick , Wren Brendan W. , Barrow Paul A. 
Published: June 2004

ABSTRACT

The genome sequence of the human pathogen
Campylobacter jejuni
NCTC11168 has been determined recently, but studies on colonization and persistence in chickens have been limited due to reports that this strain is a poor colonizer. Experimental colonization and persistence studies were carried out with
C. jejuni
NCTC11168 by using 2-week-old Light Sussex chickens possessing an acquired natural gut flora. After inoculation, NCTC11168 initially colonized the intestine poorly. However, after 5 weeks we observed adaptation to high-level colonization, which was maintained after in vitro passage. The adapted strain exhibited greatly increased motility. A second strain,
C. jejuni
11168H, which had been selected under in vitro conditions for increased motility (A. V. Karlyshev, D. Linton, N. A. Gregson, and B. W. Wren, Microbiology
148:
473-480, 2002), also showed high-level intestinal colonization. The levels of colonization were equivalent to those of six other strains, assessed under the same conditions. There were four mutations in
C. jejuni
11168H that reduced colonization;
maf5
,
flaA
(motility and flagellation), and
kpsM
(capsule deficiency) eliminated colonization, whereas
pglH
(general glycosylation system deficient) reduced but did not eliminate colonization. This study showed that there was colonization of the avian intestinal tract by a
Campylobacter
strain having a known genome sequence, and it provides a model for colonization and persistence studies with specific mutations.
RsbU-Dependent Regulation of
Staphylococcus epidermidis
Biofilm Formation Is Mediated via the Alternative Sigma Factor σ
B
by Repression of the Negative Regulator Gene
icaR
Authors: Knobloch Johannes K.-M. , Jäger Sebastian , Horstkotte Matthias A. , Rohde Holger , Mack Dietrich 
Published: June 2004

ABSTRACT

Transposon mutagenesis of
rsbU
leads to a biofilm-negative phenotype in
Staphylococcus epidermidis
. However, the pathway of this regulatory mechanism was unknown. To investigate the role of RsbU in the regulation of the alternative sigma factor σ
B
and biofilm formation, we generated different mutants of the σ
B
operon in
S. epidermidis
strains 1457 and 8400. The genes
rsbU
,
rsbV
,
rsbW
, and
sigB
, as well as the regulatory cascade
rsbUVW
and the entire σ
B
operon, were deleted. Transcriptional analysis of
sarA
and the σ
B
-dependent gene
asp23
revealed the functions of RsbU and RsbV as positive regulators and of RsbW as a negative regulator of σ
B
activity, indicating regulation of σ
B
activity similar to that characterized for
Bacillus subtilis
and
Staphylococcus aureus
. Phenotypic characterization of the mutants revealed that the dramatic decrease of biofilm formation in
rsbU
mutants is mediated via σ
B
, indicating a crucial role for σ
B
in
S. epidermidis
pathogenesis. However, biofilm formation in mutants defective in σ
B
or its function could be restored in the presence of subinhibitory ethanol concentrations. Transcriptional analysis revealed that
icaR
is up-regulated in mutants lacking σ
B
function but that
icaA
transcription is down-regulated in these mutants, indicating a σ
B
-dependent regulatory intermediate negatively regulating IcaR. Supplementation of growth media with ethanol decreased
icaR
transcription, leading to increased
icaA
transcription and a biofilm-positive phenotype, indicating that the ethanol-dependent induction of biofilm formation is mediated by IcaR. This
icaR
-dependent regulation under ethanol induction is mediated in a σ
B
-independent manner, suggesting at least one additional regulatory intermediate in the biofilm formation of
S. epidermidis
.
Overexpression of Interleukin-15 Increases Susceptibility to Lipopolysaccharide-Induced Liver Injury in Mice Primed withMycobacterium bovisBacillus Calmette-Guérin
Authors: Yajima Toshiki , Nishimura Hitoshi , Saito Kimika , Kuwano Hiroyuki , Yoshikai Yasunobu 
Published: June 2004

ABSTRACTMice primed withMycobacterium bovisbacillus Calmette-Guérin (BCG) are highly sensitive to lipopolysaccharide (LPS)-induced liver injury and lethality. We found that interleukin-15 (IL-15) transgenic (Tg) mice primed with BCG were more susceptible to LPS-induced liver injury than non-Tg mice. The numbers of CD44+CD8+T cells expressing intracellular gamma interferon (IFN-γ) significantly increased in the livers of BCG-primed IL-15 Tg mice after LPS injection, and the depletion of CD8+T cells from BCG-primed IL-15 Tg mice completely abolished the susceptibility to LPS-induced lethality. Liver T cells from BCG-primed IL-15 Tg mice produced IFN-γ in vitro in response to LPS, which was inhibited by the addition of anti-IL-12 monoclonal antibody (MAb). In vivo treatment with anti-IL-12 MAb inhibited the appearance of CD44+CD8+T cells expressing intracellular IFN-γ after LPS injection. These results suggest that the overexpression of IL-15 increases susceptibility to LPS-induced liver injury in BCG-primed mice via bystander activation of CD8+T cells.
Helicobacter pyloriwith a Truncated Lipopolysaccharide O Chain Fails To Induce Gastritis in SCID Mice Injected with Splenocytes from Wild-Type C57BL/6J Mice
Authors: Eaton K. A. , Logan S. M. , Baker P. E. , Peterson R. A. , Monteiro M. A. , Altman E. 
Published: June 2004

ABSTRACTThe goal of this study was to determine whetherHelicobacter pylorilipopolysaccharide (LPS) O-chain polysaccharide contributes to gastritis in a mouse model. C57BL/6J or C57BL/6-Prkdcscid(severe combined immunodeficient [SCID]) mice were inoculated withH. pyloristrain SS1 or SS1::0826kan, in which a β-1,4-galactosyltransferase (HP0826), an LPS biosynthetic enzyme, had been disrupted.H. pyloristrain SS1::0826kan expresses truncated LPS lacking O chain. Recipient SCID mice were given C57BL/6J splenocytes by intraperitoneal injection. Bacterial colonization, gastric lesions (gastritis, neutrophilic infiltration, and gastric epithelial metaplasia), cellular (delayed-type hypersensitivity) and humoral immune responses toH. pylorisonicate, and gastric gamma interferon (IFN-γ) mRNA expression were quantified. Recipient SCID mice colonized byH. pyloristrain SS1 developed extensive gastritis with loss of normal fundic gland morphology. In contrast, gastric mucosa of recipient SCID mice colonized byH. pyloristrain SS1::0826kan was not statistically distinguishable from that of uninfected recipient mice. Delayed-type hypersensitivity and humoral immune responses were detected in infected mice inoculated with wild-type SS1, but not with SS1::0826kan. IFN-γ transcription was lower in mice infected with SS1::0826kan than in mice infected with SS1. In this model of rapidly progressive gastritis due toH. pylori, the O chain contributed to the extent of gastritis and to the host immune response. These data support a role forH. pyloriLPS O chain in direct induction of the host immune response leading to gastritis and gastric damage and are in contrast to protein antigens, such as urease andcagproducts which do not contribute to gastritis in mice.
Oral Vaccination withBrucella melitensisWR201 Protects Mice against Intranasal Challenge with VirulentBrucella melitensis16M
Authors: Izadjoo Mina J. , Bhattacharjee Apurba K. , Paranavitana Chrysanthi M. , Hadfield Ted L. , Hoover David L. 
Published: June 2004

ABSTRACTHuman brucellosis can be acquired from infected animal tissues by ingestion, inhalation, or contamination of conjunctiva or traumatized skin by infected animal products. In addition,Brucellais recognized as a biowarfare threat agent. Although a vaccine to protect humans from natural or deliberate infection could be useful, vaccines presently used in animals are unsuitable for human use. We tested orally administered live, attenuated, purine auxotrophicB. melitensisWR201 bacteria for their ability to elicit cellular and humoral immune responses and to protect mice against intranasal challenge withB. melitensis16M bacteria. Immunized mice made serum antibody to lipopolysaccharide and non-O-polysaccharide antigens. Splenocytes from immunized animals released interleukin-2 and gamma interferon when grown in cultures withBrucellaantigens. Immunization led to protection from disseminated infection and enhanced clearance of the challenge inoculum from the lungs. Optimal protection required administration of live bacteria, was related to immunizing dose, and was enhanced by booster immunization. These results establish the usefulness of oral vaccination against respiratory challenge with virulentBrucellaand suggest that WR201 should be further investigated as a vaccine to prevent human brucellosis.
Synthetic Fragments ofVibrio choleraeO1 Inaba O-Specific Polysaccharide Bound to a Protein Carrier Are Immunogenic in Mice but Do Not Induce Protective Antibodies
Authors: Meeks Michael D. , Saksena Rina , Ma Xingquan , Wade Terri K. , Taylor Ronald K. , Kováč Pavol , Wade William F. 
Published: June 2004

ABSTRACTDevelopment ofVibrio choleraelipopolysaccharide (LPS) as a cholera vaccine immunogen is justified by the correlation of vibriocidal anti-LPS response with immunity. TwoV. choleraeO1 LPS serotypes, Inaba and Ogawa, are associated with endemic and pandemic cholera. Both serotypes induce protective antibody following infection or vaccination. Structurally, the LPSs that define the serotypes are identical except for the terminal perosamine moiety, which has a methoxyl group at position 2 in Ogawa but a hydroxyl group in Inaba. The terminal sugar of the Ogawa LPS is a protective B-cell epitope. We chemically synthesized the terminal hexasaccharides ofV. choleraeserotype Ogawa, which comprises in part the O-specific polysaccharide component of the native LPS, and coupled the oligosaccharide at different molar ratios to bovine serum albumin (BSA). Our initial studies with Ogawa immunogens showed that the conjugates induced protective antibody. We hypothesized that antibodies specific for the terminal sugar of Inaba LPS would also be protective. Neoglycoconjugates were prepared from synthetic Inaba oligosaccharides (disaccharide, tetrasaccharide, and hexasaccharide) and BSA at different levels of substitution. BALB/c mice responded to the Inaba carbohydrate (CHO)-BSA conjugates with levels of serum antibodies of comparable magnitude to those of mice immunized with Ogawa CHO-BSA conjugates, but the Inaba-specific antibodies (immunoglobulin M [IgM] and IgG1) were neither vibriocidal nor protective in the infant mouse cholera model. We hypothesize that the anti-Inaba antibodies induced by the Inaba CHO-BSA conjugates have enough affinity to be screened via enzyme-linked immunosorbent assay but not enough to be protective in vivo.
S100 and Cytokine Expression in Caries
Authors: McLachlan Julia L. , Sloan Alastair J. , Smith Anthony J. , Landini Gabriel , Cooper Paul R. 
Published: June 2004

ABSTRACT
The molecular immune response of the pulpal tissue during chronic carious infection is poorly characterized. Our objective was to examine the expression of potential molecular mediators of pulpal inflammation, correlate their levels with disease severity, and determine the cellular localization of key molecules. Results indicated that there was significantly increased transcriptional activity in carious compared to healthy pulp, and the increase correlated positively with disease severity. Semiquantitative reverse transcriptase PCR analysis in 10 carious and 10 healthy pulpal tissue samples of the S100 family members S100A8, S100A9, S100A10, S100A12, and S100A13; the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-8, IL-6, and epithelial cell-derived neutrophil attractant 78 (ENA-78); and the structural protein collagen-1α indicated that all genes tested, with the exception of S100A10, were more abundantly expressed in carious teeth. In addition, we found that the closer the carious lesion front was to the pulpal chamber the higher the expression was for all genes except S100A10. Multiple-regression analysis identified a significant positive correlation between the expression levels of S100A8 and IL-1β, ENA-78, and IL-6 and between collagen-1α and S100A8, TNF-α, IL-1β, IL-8, IL-6, and ENA-78. Immunohistochemical studies in carious pulpal tissue indicated that S100A8 and the S100A8/S100A9 complex were predominantly expressed by infiltrating neutrophils. Gene expression analyses in immune system cells supported these findings and indicated that bacterial activation of neutrophils caused upregulation of S100A8, S100A9, and S100A13. This study highlights the complex nature of the molecular immune response that occurs during carious infection.
Characterization of β-Glucan Recognition Site on C-Type Lectin, Dectin 1
Authors: Adachi Yoshiyuki , Ishii Takashi , Ikeda Yoshihiko , Hoshino Akiyoshi , Tamura Hiroshi , Aketagawa Jun , Tanaka Shigenori , Ohno Naohito 
Published: June 2004

ABSTRACTDectin 1 is a mammalian cell surface receptor for (1→3)-β-d-glucans. Since (1→3)-β-d-glucans are commonly present on fungal cell walls, it has been suggested that dectin 1 is important for recognizing fungal invasion. In this study we tried to deduce the amino acid residues in dectin 1 responsible for β-glucan recognition. HEK293 cells transfected with mouse dectin 1 cDNA could bind to a gel-forming (1→3)-β-d-glucan, schizophyllan (SPG). The binding of SPG to a dectin 1 transfectant was inhibited by pretreatment with other β-glucans having a (1→3)-β-d-glucosyl linkage but not by pretreatment with α-glucans. Dectin 1 has a carbohydrate recognition domain (CRD) consisting of six cysteine residues that are highly conserved in C-type lectins. We prepared 32 point mutants with mutations in the CRD and analyzed their binding to SPG. Mutations at Trp221and His223resulted in decreased binding to β-glucan. Monoclonal antibody 4B2, a dectin- 1 monoclonal antibody which had a blocking effect on the β-glucan interaction, completely failed to bind the dectin-1 mutant W221A. A mutant with mutations in Trp221and His223did not have a collaborative effect on Toll-like receptor 2-mediated cellular activation in response to zymosan. These amino acid residues are distinct from residues in other sugar-recognizing peptide sequences of typical C-type lectins. These results suggest that the amino acid sequence W221-I222-H223 is critical for formation of a β-glucan binding site in the CRD of dectin 1.
Contribution of Gene Loss to the Pathogenic Evolution of
Burkholderia pseudomallei
and
Burkholderia mallei
Authors: Moore Richard A. , Reckseidler-Zenteno Shauna , Kim Heenam , Nierman William , Yu Yan , Tuanyok Apichai , Warawa Jonathan , DeShazer David , Woods Donald E. 
Published: June 2004

ABSTRACT

Burkholderia pseudomallei
is the causative agent of melioidosis.
Burkholderia thailandensis
is a closely related species that can readily utilize
l
-arabinose as a sole carbon source, whereas
B. pseudomallei
cannot. We used Tn
5
-OT182 mutagenesis to isolate an arabinose-negative mutant of
B. thailandensis
. Sequence analysis of regions flanking the transposon insertion revealed the presence of an arabinose assimilation operon consisting of nine genes. Analysis of the
B. pseudomallei
chromosome showed a deletion of the operon from this organism. This deletion was detected in all
B. pseudomallei
and
Burkholderia mallei
strains investigated. We cloned the
B. thailandensis
E264 arabinose assimilation operon and introduced the entire operon into the chromosome of
B. pseudomallei
406e via homologous recombination. The resultant strain,
B. pseudomallei
SZ5028, was able to utilize
l
-arabinose as a sole carbon source. Strain SZ5028 had a significantly higher 50% lethal dose for Syrian hamsters compared to the parent strain 406e. Microarray analysis revealed that a number of genes in a type III secretion system were down-regulated in strain SZ5028 when cells were grown in
l
-arabinose, suggesting a regulatory role for
l
-arabinose or a metabolite of
l
-arabinose. These results suggest that the ability to metabolize
l
-arabinose reduces the virulence of
B. pseudomallei
and that the genes encoding arabinose assimilation may be considered antivirulence genes. The increase in virulence associated with the loss of these genes may have provided a selective advantage for
B. pseudomallei
as these organisms adapted to survival in animal hosts.
Response of the Splenic Dendritic Cell Population to Malaria Infection
Authors: Leisewitz Andrew L. , Rockett Kirk A. , Gumede Bonginkosi , Jones Margaret , Urban Britta , Kwiatkowski Dominic P. 
Published: June 2004

ABSTRACTDendritic cells, particularly those residing in the spleen, are thought to orchestrate acquired immunity to malaria, but it is not known how the splenic dendritic cell population responds to malaria infection and how this response compares with the responses of other antigen-presenting cells. We investigated this question forPlasmodium chabaudiAS infection in C57BL/6 mice. We found that dendritic cells, defined here by the CD11c marker, migrated from the marginal zone of the spleen into the CD4+T-cell area within 5 days after parasites entered the bloodstream. This contrasted with the results observed for the macrophage and B-cell populations, which expanded greatly but did not show any comparable migration. Over the same time period dendritic cells showed upregulation of CD40, CD54, and CD86 costimulatory molecules that are required for successful T-cell activation. In dendritic cells, the peak intracellular gamma interferon expression (as shown by fluorescence-activated cell sorting) was on day 5, 2 days earlier than the peak expression in B-cells or macrophages. These findings show that splenic dendritic cells are actively engaged in the earliest phase of malarial infection in vivo and are likely to be critical in shaping the subsequent immune response.
Transcriptional Responses of Intestinal Epithelial Cells to Infection with
Vibrio cholerae
Authors: Stokes Neil R. , Zhou Xin , Meltzer Stephen J. , Kaper James B. 
Published: June 2004

ABSTRACT

Vibrio cholerae
is a noninvasive enteric bacterium that causes the severe diarrheal disease cholera. Candidate cholera vaccines have been engineered by deleting genes encoding known virulence factors in
V. cholerae
; however, many of these attenuated strains were still reactogenic in human volunteers. In this study, DNA arrays were utilized to monitor the transcriptional responses of human intestinal epithelial cells (T84) to eight strains of
V. cholerae
, including attenuated, toxigenic, and environmental isolates. cDNA probes generated from host RNA samples were hybridized against low- and high-density gene arrays.
V. cholerae
induced the transcription of a variety of host genes and repressed the expression of a lower number of genes. Expression patterns were confirmed for certain genes by reverse transcriptase PCR and enzyme-linked immunosorbent assays. A core subset of genes was found to be differentially regulated in all experiments. These genes included genes involved in innate mucosal immunity, intracellular signaling, and cellular proliferation. Reactogenic vaccine strains induced greater expression of genes for certain proinflammatory cytokines than nonreactogenic strains. Wild-type and attenuated derivatives induced and repressed many genes in common, although there were differences in the transcription profiles. These results indicate that the types of host genes modulated by attenuated
V. cholerae
, and the extent of their induction, may mediate the symptoms seen with reactogenic cholera vaccine strains.