bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive Value of Pharmacokinetics-Adjusted Phenotypic Susceptibility on Response to Ritonavir-Enhanced Protease Inhibitors (PIs) in Human Immunodeficiency Virus-Infected Subjects Failing Prior PI Therapy
Authors: Eron Joseph J. , Park Jeong-Gun , Haubrich Richard , Aweeka Francesca , Bastow Barbara , Pakes Gary E. , Yu Song , Wu Hulin , Richman Douglas D. 
Published: March 2009

ABSTRACTThe activities of protease inhibitors in vivo may depend on plasma concentrations and viral susceptibility. This nonrandomized, open-label study evaluated the relationship of the inhibitory quotient (IQ [the ratio of drug exposure to viral phenotypic susceptibility]) to the human immunodeficiency virus type 1 (HIV-1) viral load (VL) change for ritonavir-enhanced protease inhibitors (PIs). Subjects on PI-based regimens replaced their PIs with ritonavir-enhanced indinavir (IDV/r) 800/200 mg, fosamprenavir (FPV/r) 700/100 mg, or lopinavir (LPV/r) 400/200 mg twice daily. Pharmacokinetics were assessed at day 14; follow-up lasted 24 weeks. Associations between IQ and VL changes were examined. Fifty-three subjects enrolled, 12 on IDV/r, 33 on FPV/r, and 8 on LPV/r. Median changes (n-fold) (FC) of 50% inhibitory concentrations (IC50s) to the study PI were high. Median 2-week VL changes were −0.7, −0.1, and −1.0 log10for IDV/r, FPV/r, and LPV/r. With FPV/r, correlations between the IQ and the 2-week change in VL were significant (Spearman'srrange, −0.39 to −0.50;P≤ 0.029). The strongest correlation with response to FPV/r was the IC50FC (r= 0.57;P= 0.001), which improved when only adherent subjects were included (r= 0.68;P= 0.001). In multivariable analyses of the FPV/r arm that included FC, one measure of the drug concentration, corresponding IQ, baseline VL, and CD4, the FC to FPV was the only significant predictor of VL decline (P< 0.001). In exploratory analyses of all arms, the area under the concentration-time curve IQ was correlated with the week 2 VL change (r= −0.72;P< 0.001). In conclusion, in PI-experienced subjects with highly resistant HIV-1, short-term VL responses to RTV-enhanced FPV/r correlated best with baseline susceptibility. The IQ improved correlation in analyses of all arms where a greater range of virologic responses was observed.
Evaluation of Cefotaxime and Desacetylcefotaxime Concentrations in Cord Blood after Intrapartum Prophylaxis with Cefotaxime
Authors: Lepercq Jacques , Treluyer Jean Marc , Auger Christelle , Raymond Josette , Rey Elisabeth , Schmitz Thomas , Jullien Vincent 
Published: March 2009

ABSTRACT

Preterm premature rupture of the membranes is associated with a high risk of neonatal sepsis. An increase in the incidence of early-onset neonatal sepsis due to ampicillin-resistant
Escherichia coli
in premature infants has been observed in the past few years. Intrapartum prophylaxis with ampicillin has proven to be efficient for the prevention of early neonatal sepsis due to group B streptococci. To date, there is no strategy for the prevention of early neonatal sepsis due to ampicillin-resistant
E. coli
. Our aim was to investigate whether a standardized dosage regimen of intrapartum cefotaxime could provide concentrations in the cord blood greater than the cefotaxime MIC
90
for
E. coli
. Seven pregnant women hospitalized with preterm premature rupture of the membranes and colonized with ampicillin-resistant isolates of the family
Enterobacteriaceae
were included. Cefotaxime was given intravenously during delivery, as follows: 2 g at the onset of labor and then 1 g every 4 h until delivery. Blood specimens were collected from the mother 30 min after the first injection and just before the second injection, and at birth, blood specimens were simultaneously collected from the mother and the umbilical cord. The concentrations of cefotaxime in the cord blood ranged from 0.5 to 8.5 mg/liter. The MIC
90
of cefotaxime for
E. coli
strains (0.125 mg/liter) was achieved in all cases. This preliminary study supports the use of cefotaxime for intrapartum prophylaxis in women colonized with ampicillin-resistant isolates of
Enterobacteriaceae
. The effectiveness of this regimen for the prevention of neonatal sepsis needs to be evaluated with a larger population.
Atorvastatin Is a Promising Partner for Antimalarial Drugs in Treatment of
Plasmodium falciparum
Malaria
Authors: Parquet Véronique , Briolant Sébastien , Torrentino-Madamet Marylin , Henry Maud , Almeras Lionel , Amalvict Rémy , Baret Eric , Fusaï Thierry , Rogier Christophe , Pradines Bruno 
Published: March 2009

ABSTRACT

Atorvastatin (AVA) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. AVA exposure resulted in the reduced in vitro growth of 22
Plasmodium falciparum
strains, with the 50% inhibitory concentrations (IC
50
s) ranging from 2.5 μM to 10.8 μM. A significant positive correlation was found between the strains’ responses to AVA and mefloquine (
r
= 0.553;
P
= 0.008). We found no correlation between the responses to AVA and to chloroquine, quinine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, or doxycycline. These data could suggest that the mechanism of AVA uptake and/or the mode of action of AVA is different from those for other antimalarial drugs. The IC
50
s for AVA were unrelated to the occurrence of mutations in the transport protein genes involved in quinoline antimalarial drug resistance, such as the
P. falciparum crt
,
mdr1
,
mrp
, and
nhe-1
genes. Therefore, AVA can be ruled out as a substrate for the transport proteins (CRT, Pgh1, and MRP) and is not subject to the pH modification induced by the
P. falciparum
NHE-1 protein. The absence of in vitro cross-resistance between AVA and chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, and doxycycline argues that these antimalarial drugs could potentially be paired with AVA as a treatment for malaria. In conclusion, the present observations suggest that AVA is a good candidate for further studies on the use of statins in association with drugs known to have activities against the malaria parasite.
Intracellular Localization of the ABCC Proteins of
Leishmania
and Their Role in Resistance to Antimonials
Authors: Leprohon Philippe , Légaré Danielle , Ouellette Marc 
Published: March 2009

ABSTRACT

The ABCC subfamily of proteins is composed of nine members in
Leishmania
. We report that all of these proteins have an intracellular localization and that the overexpression of at least four members, ABCC3, ABCC4, ABCC5, and ABCC7, can confer resistance to antimonials, the first-line drug against
Leishmania
.
Omeprazole Antagonizes Virulence and Inflammation in
Salmonella enterica
-Infected RAW264.7 Cells
Authors: Puiac Speranta , Negrea Aurel , Richter-Dahlfors Agneta , Plant Laura , Rhen Mikael 
Published: March 2009

ABSTRACT

The proton pump inhibitor omeprazole reduced the intracellular replication of
Salmonella enterica
serovar Typhimurium in RAW264.7 cells without affecting bacterial growth in vitro or the viability of the host cells. The mechanism was bacteriostatic and interfered with replication mediated by the virulence-associated SPI2 type III secretion system. The proton pump inhibitor bafilomycin A
1
, in contrast, mediated killing of intracellular bacteria and imposed a marked cytotoxicity on RAW264.7 cells. The two compounds also differentially affected the proinflammatory responses of the infected cells. Bafilomycin A
1
enhanced nitric oxide production, whereas omeprazole delayed IκB degradation and blocked nitric oxide production and the secretion of proinflammatory cytokines. These results imply that omeprazole can be used to block the virulence factor-mediated intracellular replication of
S
. Typhimurium, and that its mechanism of growth inhibition is different from that mediated by bafilomycin A
1
.
Inhibition of Vaccinia Virus Replication by Two Small Interfering RNAs Targeting B1R and G7L Genes and Their Synergistic Combination with Cidofovir
Authors: Vigne Solenne , Duraffour Sophie , Andrei Graciela , Snoeck Robert , Garin Daniel , Crance Jean-Marc 
Published: March 2009

ABSTRACTIn view of the threat of the potential use of variola virus in a terrorist attack, considerable efforts have been performed to develop new antiviral strategies against orthopoxviruses. Here we report on the use of RNA interference, either alone or in combination with cidofovir, as an approach to inhibit orthopoxvirus replication. Two selected small interfering RNAs (siRNAs), named siB1R-2 and siG7L-1, and a previously reported siRNA, i.e., siD5R-2 (which targets the viral D5R mRNA), were evaluated for antiviral activity against vaccinia virus (VACV) by plaque reduction and virus yield assays. siB1R-2 and siG7L-1, administered before or after viral infection, reduced VACV replication by more than 90%. Also, these two siRNAs decreased monkeypox virus replication by 95% at a concentration of 1 nM. siB1R-2 and siG7L-1 were demonstrated to specifically silence their corresponding transcripts, i.e., B1R and G7L mRNAs, without induction of a beta interferon response. Strong synergistic effects were observed when siB1R-2, siG7L-1, or siD5R-2 was combined with cidofovir. In addition, the antiviral activities of these three siRNAs were evaluated against VACV resistant to cidofovir and other acyclic nucleoside phosphonates. siG7L-1 and siD5R-2 remained active against four of five VACV mutants, while siB1R-2 showed activity against only one of the mutants. Our results showed that siRNAs are potent inhibitory agents in vitro, not only against wild-type VACV but also against several cidofovir-resistant VACV. Furthermore, we showed that a combined therapy using siRNA and cidofovir may be useful in the treatment of poxvirus infections.
Antibodies to Reticulocyte Binding Protein-Like Homologue 4 Inhibit Invasion of
Plasmodium falciparum
into Human Erythrocytes
Authors: Tham Wai-Hong , Wilson Danny W. , Reiling Linda , Chen Lin , Beeson James G. , Cowman Alan F. 
Published: March 2009

ABSTRACT

Plasmodium falciparum
invasion into human erythrocytes relies on the interaction between multiple parasite ligands and their respective erythrocyte receptors. The sialic acid-independent invasion pathway is dependent on the expression of
P. falciparum
reticulocyte binding protein-like homologue 4 (PfRh4), as disruption of the gene abolishes the ability of parasites to switch to this pathway. We show that PfRh4 is present as an invasion ligand in culture supernatants as a 160-kDa proteolytic fragment. We confirm that PfRh4 binds to the surfaces of erythrocytes through recognition of an erythrocyte receptor that is neuraminidase resistant but trypsin and chymotrypsin sensitive. Serum antibodies from malaria-exposed individuals show reactivity against the binding domain of PfRh4. Purified immunoglobulin G raised in rabbits against the binding domain of PfRh4 blocked the binding of native PfRh4 to the surfaces of erythrocytes and inhibited erythrocyte invasion of parasites using sialic acid-independent invasion pathways and grown in neuraminidase-treated erythrocytes. Our results suggest PfRh4 is a potential vaccine candidate.
Induction of Adhesion-Inhibitory Antibodies against PlacentalPlasmodium falciparumParasites by Using Single Domains of VAR2CSA
Authors: Nielsen Morten A. , Pinto Vera V. , Resende Mafalda , Dahlbäck Madeleine , Ditlev Sisse B. , Theander Thor G. , Salanti Ali 
Published: March 2009

ABSTRACTIn areas of endemicity pregnancy-associated malaria is an important cause of maternal anemia, stillbirth, and delivery of low-birth-weight children. The syndrome is precipitated by the accumulation ofPlasmodium falciparum-infected erythrocytes in the placenta, mediated through an interaction between a parasite protein expressed on erythrocytes named variant surface antigen 2-chondroitin sulfate A (VAR2CSA) and CSA on syncytiotrophoblasts. VAR2CSA is a large polymorphic protein consisting of six Duffy binding-like (DBL), domains and with current constraints on recombinant protein production it is not possible to produce entire VAR2CSA recombinant proteins. Furthermore, the presence of polymorphisms has raised the question of whether it is feasible to define VAR2CSA antigens eliciting broadly protective antibodies. Thus, the challenge for vaccine development is to define smaller parts of the molecule which induce antibodies that inhibit CSA binding of different parasite strains. In this study, we produced a large panel of VAR2CSA proteins and raised antibodies against these antigens. We show that antibodies against the DBL4 domain effectively inhibit parasite binding. As the inhibition was not limited to homologous parasite strains, it seems feasible to base a protective malaria vaccine on a single VAR2CSA DBL domain.
Cytolethal Distending Toxin PromotesHelicobacter cinaedi-Associated Typhlocolitis in Interleukin-10-Deficient Mice
Authors: Shen Z. , Feng Y. , Rogers A. B. , Rickman B. , Whary M. T. , Xu S. , Clapp K. M. , Boutin S. R. , Fox J. G. 
Published: March 2009

ABSTRACTHelicobacter cinaedicolonizes a wide host range, including rodents, and may be an emerging zoonotic agent. Colonization parameters, pathology, serology, and inflammatory responses to wild-typeH. cinaedi(WTHc) were evaluated in B6.129P2-IL-10tm1Cgn(IL-10−/−) mice for 36 weeks postinfection (WPI) and in C57BL/6 (B6) mice for 12 WPI. Because cytolethal distending toxin (CDT) may be a virulence factor, IL-10−/−mice were also infected with thecdtBHcandcdtB-NHcisogenic mutants and evaluated for 12 WPI. Consistent with other murine enterohepatic helicobacters, WTHcdid not cause typhlocolitis in B6 mice, but mild to severe lesions developed at the cecocolic junction in IL-10−/−mice, despite similar colonization levels of WTHcin the cecum and colon of both B6 and IL-10−/−mice. WTHcandcdtBmutants also colonized IL-10−/−mice to a similar extent, but infection with eithercdtBmutant resulted in attenuated typhlocolitis and hyperplasia compared to infection with WTHc(P< 0.03), and only WTHcinfection caused dysplasia and intramucosal carcinoma. WTHcandcdtBHcmutant infection of IL-10−/−mice elevated mRNA expression of tumor necrosis factor alpha, inducible nitric oxide synthase, and gamma interferon in the cecum, as well as elevated Th1-associated serum immunoglobulin G2abcompared to infection of B6 mice (P< 0.05). Although no hepatitis was noted, liver samples were PCR positive at various time points for WTHcor thecdtBHcmutant in approximately 33% of IL-10−/−mice and in 10 to 20% of WTHc-infected B6 mice. These results indicate that WTHccan be used to model inflammatory bowel disease in IL-10−/−mice and that CDT contributes to the virulence ofH. cinaedi.
Bacillus anthracisEdema Toxin Suppresses Human Macrophage Phagocytosis and Cytoskeletal Remodeling via the Protein Kinase A and Exchange Protein Activated by Cyclic AMP Pathways
Authors: Yeager Linsey A. , Chopra Ashok K. , Peterson Johnny W. 
Published: March 2009

ABSTRACTBacillus anthracis, the etiological agent of anthrax, is a gram-positive spore-forming bacterium. It produces edema toxin (EdTx), a powerful adenylate cyclase that increases cyclic AMP (cAMP) levels in host cells. Because other cAMP-increasing agents inhibit key macrophage (MΦ) functions, such as phagocytosis, it was hypothesized that EdTx would exhibit similar suppressive activities. Our previous GeneChip data showed that EdTx downregulated MΦ genes involved in actin cytoskeleton remodeling, including protein kinase A (PKA). To further examine the role of EdTx during anthrax pathogenesis, we explored the hypothesis that EdTx treatment leads to deregulation of the cAMP-dependent PKA system, resulting in impaired cytoskeletal functions essential for MΦ activity. Our data revealed that EdTx significantly suppressed human MΦ phagocytosis of Ames spores. Cytoskeletal changes, such as decreased cell spreading and lowered F-actin content, were also observed for toxin-treated MΦs. Further, EdTx altered the protein levels and activity of PKA and exchange protein activated by cAMP (Epac), a recently identified cAMP-binding molecule. By using PKA- and Epac-selective cAMP analogs, we confirmed the involvement of both pathways in the inhibition of MΦ functions elicited by EdTx-generated cAMP. These results suggested that EdTx weakened the host immune response by increasing cAMP levels, which then signaled via PKA and Epac to cripple MΦ phagocytosis and interfered with cytoskeletal remodeling.
Resistance ofCapnocytophaga canimorsusto Killing by Human Complement and Polymorphonuclear Leukocytes
Authors: Shin Hwain , Mally Manuela , Meyer Salome , Fiechter Chantal , Paroz Cécile , Zaehringer Ulrich , Cornelis Guy R. 
Published: March 2009

ABSTRACTCapnocytophaga canimorsusis a bacterium of the canine oral flora known since 1976 to cause rare but severe septicemia and peripheral gangrene in patients that have been in contact with a dog. It was recently shown that these bacteria do not elicit an inflammatory response (H. Shin, M. Mally, M. Kuhn, C. Paroz, and G. R. Cornelis, J. Infect. Dis. 195:375-386, 2007). Here, we analyze their sensitivity to the innate immune system. Bacteria from the archetype strain Cc5 were highly resistant to killing by complement. There was little membrane attack complex (MAC) deposition in spite of C3b deposition. Cc5 bacteria were as resistant to phagocytosis by human polymorphonuclear leukocytes (PMNs) asYersinia enterocoliticaMRS40, endowed with an antiphagocytic type III secretion system. We isolated Y1C12, a transposon mutant that is hypersensitive to killing by complement via the antibody-dependent classical pathway. The mutation inactivated a putative glycosyltransferase gene, suggesting that the Y1C12 mutant was affected at the level of a capsular polysaccharide or lipopolysaccharide (LPS) structure. Cc5 appeared to have several polysaccharidic structures, one being altered in Y1C12. The structure missing in Y1C12 could be purified by classical LPS purification procedures and labeled by tritiated palmitate, indicating that it is more likely to be an LPS structure than a capsule. Y1C12 bacteria were also more sensitive to phagocytosis by PMNs than wild-type bacteria. In conclusion, a polysaccharide structure, likely an LPS, protectsC. canimorsusfrom deposition of the complement MAC and from efficient phagocytosis by PMNs.
Campylobacter jejuni
Glycosylation Island Important in Cell Charge, Legionaminic Acid Biosynthesis, and Colonization of Chickens
Authors: Howard Sarah L. , Jagannathan Aparna , Soo Evelyn C. , Hui Joseph P. M. , Aubry Annie J. , Ahmed Imran , Karlyshev Andrey , Kelly John F. , Jones Michael A. , Stevens Mark P. , Logan Susan M. , Wren Brendan W. 
Published: March 2009

ABSTRACT

Previously, we identified five genes (Cj1321 to Cj1326, of which Cj1325 and Cj1326 are a single gene) in the O-linked flagellin glycosylation island that are highly prevalent in
Campylobacter jejuni
isolates from chickens. We report mutagenesis, functional, and structural data to confirm that this locus, and Cj1324 in particular, has a significant contributory role in the colonization of chickens by
C. jejuni
. A motile ΔCj1324 mutant with intact flagella was considerably less hydrophobic and less able to autoagglutinate and form biofilms than the parent strain, 11168H, suggesting that the surface charge of flagella of Cj1324-deficient strains was altered. The physical and functional attributes of the parent were restored upon complementation. Structural analysis of flagellin protein purified from the ΔCj1324 mutant revealed the absence of two legionaminic acid glycan modifications that were present in the parent strain, 11168H. These glycoform modifications were shown to be prevalent in chicken isolates and confirm that differences in the highly variable flagellin glycosylation locus can relate to the strain source. The discovery of molecular mechanisms influencing the persistence of
C. jejuni
in poultry aids the rational design of approaches to control this problematic pathogen in the food chain.
Antibody-Enhanced, Fc Gamma Receptor-Mediated Endocytosis of
Clostridium difficile
Toxin A
Authors: He Xiangyun , Sun Xingmin , Wang Jufang , Wang Xiaoning , Zhang Quanshun , Tzipori Saul , Feng Hanping 
Published: March 2009

ABSTRACT

Toxin A (TcdA) and toxin B (TcdB) are major virulence factors of
Clostridium difficile
. These two toxins intoxicate cultured cells by similar mechanisms, and TcdB generally is more potent than TcdA in cultured cells. The exact reason for this difference is unclear. Here, we report that the cellular effects of TcdA can be substantially enhanced via an opsonizing antibody through Fc gamma receptor I (FcγRI)-mediated endocytosis. A TcdA-specific monoclonal antibody, A1H3, was found to significantly enhance the cytotoxicity of TcdA to macrophages and monocytes. The A1H3-dependent enhancement of glucosyltransferase activity, cytoskeleton disruption, and tumor necrosis factor alpha production induced by TcdA was further demonstrated using RAW 264.7 cells. Subsequent experiments indicated that the interaction of FcγRI with A1H3 underlays the antibody-dependent enhancement of the cellular effects of TcdA. While blocking FcγRII and FcγRIII with anti-CD16/32 antibodies did not affect the TcdA-mediated glucosylation of Rac1 in RAW 264.7 cells, presaturation of FcγRI with anti-CD64 antibodies in THP1 cells significantly reduced this activity. Incubation of a TcdA-A1H3 immune complex with recombinant mouse CD64 completely abrogated the A1H3-mediated enhancement of the glucosyltransferase activity of TcdA in RAW 264.7 cells. Moreover, expression of FcγRI in CHO cells strikingly enhanced the sensitivity of these cells to TcdA complexed with A1H3. We showed that the presence of A1H3 facilitated cell surface recruitment of TcdA, contributing to the antibody-dependent, FcγRI-mediated enhancement of TcdA activity. Finally, studies using chlorpromazine and endosomal acidification inhibitors revealed an important role of the endocytic pathway in the A1H3-dependent enhancement of TcdA activity.