bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria
Authors: Tarning Joel , Rijken Marcus J. , McGready Rose , Phyo Aung Pyae , Hanpithakpong Warunee , Day Nicholas P. J. , White Nicholas J. , Nosten François , Lindegardh Niklas 
Published: January 2012

ABSTRACT
Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.
Randomized, Double-Blind, Placebo-Controlled Trial of Monthly versus Bimonthly Dihydroartemisinin-Piperaquine Chemoprevention in Adults at High Risk of Malaria
Authors: Lwin Khin Maung , Phyo Aung Pyae , Tarning Joel , Hanpithakpong Warunee , Ashley Elizabeth A. , Lee Sue J. , Cheah Phaikyeong , Singhasivanon Pratap , White Nicholas J. , Lindegårdh Niklas , Nosten François 
Published: January 2012

ABSTRACT

Intermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day-treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49
Plasmodium falciparum
, 63
P. vivax
, and 2
P. ovale)
. The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both,
P
< 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (
P
< 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area where
P. vivax
and multidrug-resistant
P. falciparum
malaria are endemic.
Structural and Inhibition Studies of the RNase H Function of Xenotropic Murine Leukemia Virus-Related Virus Reverse Transcriptase
Authors: Kirby Karen A. , Marchand Bruno , Ong Yee Tsuey , Ndongwe Tanyaradzwa P. , Hachiya Atsuko , Michailidis Eleftherios , Leslie Maxwell D. , Sietsema Daniel V. , Fetterly Tracy L. , Dorst Christopher A. , Singh Kamalendra , Wang Zhengqiang , Parniak Michael A. , Sarafianos Stefan G. 
Published: January 2012

ABSTRACT

RNase H inhibitors (RNHIs) have gained attention as potential HIV-1 therapeutics. Although several RNHIs have been studied in the context of HIV-1 reverse transcriptase (RT) RNase H, there is no information on inhibitors that might affect the RNase H activity of other RTs. We performed biochemical, virological, crystallographic, and molecular modeling studies to compare the RNase H function and inhibition profiles of the gammaretroviral xenotropic murine leukemia virus-related virus (XMRV) and Moloney murine leukemia virus (MoMLV) RTs to those of HIV-1 RT. The RNase H activity of XMRV RT is significantly lower than that of HIV-1 RT and comparable to that of MoMLV RT. XMRV and MoMLV, but not HIV-1 RT, had optimal RNase H activities in the presence of Mn
2+
and not Mg
2+
. Using hydroxyl-radical footprinting assays, we demonstrated that the distance between the polymerase and RNase H domains in the MoMLV and XMRV RTs is longer than that in the HIV-1 RT by ∼3.4 Å. We identified one naphthyridinone and one hydroxyisoquinolinedione as potent inhibitors of HIV-1 and XMRV RT RNases H with 50% inhibitory concentrations ranging from ∼0.8 to 0.02 μM. Two acylhydrazones effective against HIV-1 RT RNase H were less potent against the XMRV enzyme. We also solved the crystal structure of an XMRV RNase H fragment at high resolution (1.5 Å) and determined the molecular details of the XMRV RNase H active site, thus providing a framework that would be useful for the design of antivirals that target RNase H.
Population Pharmacokinetics of Metronidazole Evaluated Using Scavenged Samples from Preterm Infants
Authors: Cohen-Wolkowiez Michael , Ouellet Daniele , Smith P. Brian , James Laura P. , Ross Ashley , Sullivan Janice E. , Walsh Michele C. , Zadell Arlene , Newman Nancy , White Nicole R. , Kashuba Angela D. M. , Benjamin Daniel K. 
Published: January 2012

ABSTRACT

Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were ≤32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 × (weight/1.5) × (PMA/32)
2.49
using a volume of distribution (
V
) (liter) of 1.07 × (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations.
Polymorphisms in the
lcrV
Gene of Yersinia enterocolitica and Their Effect on Plague Protective Immunity
Authors: Miller Nathan C. , Quenee Lauriane E. , Elli Derek , Ciletti Nancy A. , Schneewind Olaf 
Published: January 2012

ABSTRACT

Current efforts to develop plague vaccines focus on LcrV, a polypeptide that resides at the tip of type III secretion needles. LcrV-specific antibodies block
Yersinia pestis
type III injection of Yop effectors into host immune cells, thereby enabling phagocytes to kill the invading pathogen. Earlier work reported that antibodies against
Y. pestis
LcrV cannot block type III injection by
Yersinia enterocolitica
strains and suggested that
lcrV
polymorphisms may provide for escape from LcrV-mediated plague immunity. We show here that polyclonal or monoclonal antibodies raised against
Y. pestis
KIM D27 LcrV (LcrV
D27
) bind LcrV from
Y. enterocolitica
O:9 strain W22703 (LcrV
W22703
) or O:8 strain WA-314 (LcrV
WA-314
) but are otherwise unable to block type III injection by
Y. enterocolitica
strains. Replacing the
lcrV
gene on the pCD1 virulence plasmid of
Y. pestis
KIM D27 with either

lcrV
W22703

or

lcrV
WA-314

does not affect the ability of plague bacteria to secrete proteins via the type III pathway, to inject Yops into macrophages, or to cause lethal plague infections in mice. LcrV
D27
-specific antibodies blocked type III injection by
Y. pestis
expressing

lcrV
W22703

or

lcrV
WA-314

and protected mice against intravenous lethal plague challenge with these strains. Thus, although antibodies raised against LcrV
D27
are unable to block the type III injection of
Y. enterocolitica
strains, expression of

lcrV
W22703

or

lcrV
WA-314

in
Y. pestis
did not allow these strains to escape LcrV-mediated plague protective immunity in the intravenous challenge model.
Molecular Characterizations of Cytolethal Distending Toxin Produced by Providencia alcalifaciens Strains Isolated from Patients with Diarrhea
Authors: Shima Ayaka , Hinenoya Atsushi , Asakura Masahiro , Sugimoto Norihiko , Tsukamoto Teizo , Ito Hideaki , Nagita Akira , Faruque Shah M. , Yamasaki Shinji 
Published: January 2012

ABSTRACT

Cytolethal distending toxins (CDTs), which block eukaryotic cell proliferation by acting as inhibitory cyclomodulins, are produced by diverse groups of Gram-negative bacteria. Active CDT is composed of three polypeptides—CdtA, CdtB, and CdtC—encoded by the genes
cdtA
,
cdtB
, and
cdtC
, respectively. We developed a PCR-restriction fragment length polymorphism assay for the detection and differentiation of five alleles of
cdtB
(Cdt-I through Cdt-V) in
Escherichia coli
and used the assay to investigate the prevalence and characteristic of CDT-producing
E. coli
in children with diarrhea (A. Hinenoya et al., Microbiol. Immunol. 53:206–215, 2009). In these assays, two untypable
cdtB
genes were detected and the organisms harboring the
cdtB
gene were identified as
Providencia alcalifaciens
(strains AH-31 and AS-1). Nucleotide sequence analysis of the
cdt
gene cluster revealed that the
cdtA
,
cdtB
, and
cdtC
genes of
P. alcalifaciens
are of 750, 810, and 549 bp, respectively. To understand the possible horizontal transfer of the
cdt
genes among closely related species, the presence of
cdt
genes was screened in various
Providencia
spp. by colony hybridization assay, and the
cdt
gene cluster was found in only limited strains of
P. alcalifaciens
. Genome walking revealed that the
cdt
gene cluster of
P. alcalifaciens
is located adjacent to a putative transposase gene, suggesting the locus might be horizontally transferable. Interestingly, the CDT of
P. alcalifaciens
(PaCDT) showed some homology with the CDT of
Shigella boydii
. Whereas filter-sterilized lysates of strains AH-31 and AS-1 showed distention of CHO but not of HeLa cells,
E. coli
CDT-I exhibited distention of both cells. This activity of PaCDT was confirmed by generating recombinant PaCDT protein, which could also be neutralized by rabbit anti-PaCdtB antibody. Furthermore, recombinant PaCDT was found to induce G
2
/M cell cycle arrest and phosphorylation of host histone H2AX, a sensitive marker of DNA double-strand breaks. To our knowledge, this is the first report showing that certain clinical
P. alcalifaciens
strains could produce variants of the CDTs compared.
Plasmodium yoelii Macrophage Migration Inhibitory Factor Is Necessary for Efficient Liver-Stage Development
Authors: Miller Jessica L. , Harupa Anke , Kappe Stefan H. I. , Mikolajczak Sebastian A. 
Published: January 2012

ABSTRACTMammalian macrophage migration inhibitory factor (MIF) is a multifaceted cytokine involved in both extracellular and intracellular functions. Malaria parasites express a MIF homologue that might modulate host immune responses against blood-stage parasites, but the potential importance of MIF against other life cycle stages remains unstudied. In this study, we characterized the MIF homologue ofPlasmodium yoeliithroughout the life cycle, with emphasis on preerythrocytic stages.P. yoeliiMIF (Py-MIF) was expressed in blood-stage parasites and detected at low levels in mosquito salivary gland sporozoites. MIF expression was strong throughout liver-stage development and localized to the cytoplasm of the parasite, with no evidence of release into the host hepatocyte. To examine the importance of Py-MIF for liver-stage development, we generated a Py-mifknockout parasite (P. yoeliiΔmif).P. yoeliiΔmifparasites grew normally as asexual erythrocytic-stage parasites and showed normal infection of mosquitoes. In contrast, theP. yoeliiΔmifstrain was attenuated during the liver stage. Mice infected withP. yoeliiΔmifsporozoites either did not develop blood-stage parasitemia or exhibited a delay in the onset of blood-stage patency. Furthermore,P. yoeliiΔmifparasites exhibited growth retardationin vivo. Combined, the data indicate thatPlasmodiumMIF is important for liver-stage development ofP. yoelii, during which it is likely to play an intrinsic role in parasite development rather than modulating host immune responses to infection.
Hypoxia-Mediated Impairment of the Mitochondrial Respiratory Chain Inhibits the Bactericidal Activity of Macrophages
Authors: Wiese Melanie , Gerlach Roman G. , Popp Isabel , Matuszak Jasmin , Mahapatro Mousumi , Castiglione Kirstin , Chakravortty Dipshikha , Willam Carsten , Hensel Michael , Bogdan Christian , Jantsch Jonathan 
Published: January 2012

ABSTRACTIn infected tissues oxygen tensions are low. As innate immune cells have to operate under these conditions, we analyzed the ability of macrophages (Mϕ) to killEscherichia coliorStaphylococcus aureusin a hypoxic microenvironment. Oxygen restriction did not promote intracellular bacterial growth but did impair the bactericidal activity of the host cells against both pathogens. This correlated with a decreased production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates. Experiments with phagocyte NADPH oxidase (PHOX) and inducible NO synthase (NOS2) double-deficient Mϕ revealed that inE. coli- orS. aureus-infected cells the reduced antibacterial activity during hypoxia was either entirely or partially independent of the diminished PHOX and NOS2 activity. Hypoxia impaired the mitochondrial activity of infected Mϕ. Inhibition of the mitochondrial respiratory chain activity during normoxia (using rotenone or antimycin A) completely or partially mimicked the defective antibacterial activity observed in hypoxicE. coli- orS. aureus-infected wild-type Mϕ, respectively. Accordingly, inhibition of the respiratory chain ofS. aureus-infected, normoxic PHOX−/−NOS2−/−Mϕ further raised the bacterial burden of the cells, which reached the level measured in hypoxic PHOX−/−NOS2−/−Mϕ cultures. Our data demonstrate that the reduced killing ofS. aureusorE. coliduring hypoxia is not simply due to a lack of PHOX and NOS2 activity but partially or completely results from an impaired mitochondrial antibacterial effector function. Since pharmacological inhibition of the respiratory chain raised the generation of ROI but nevertheless phenocopied the effect of hypoxia, ROI can be excluded as the mechanism underlying the antimicrobial activity of mitochondria.
Interplay between Candida albicans and the Mammalian Innate Host Defense
Authors: Cheng Shih-Chin , Joosten Leo A. B. , Kullberg Bart-Jan , Netea Mihai G. 
Published: January 2012

ABSTRACTCandida albicansis both the most common fungal commensal microorganism in healthy individuals and the major fungal pathogen causing high mortality in at-risk populations, especially immunocompromised patients. In this review, we summarize the interplay between the host innate system andC. albicans, ranging from how the host recognizes, responds, and clearsC. albicansinfection to howC. albicansevades, dampens, and escapes from host innate immunity.
Analysis of Cell Cycle and Replication of Mouse Macrophages after
In Vivo
and
In Vitro
Cryptococcus neoformans Infection Using Laser Scanning Cytometry
Authors: Coelho Carolina , Tesfa Lydia , Zhang Jinghang , Rivera Johanna , Gonçalves Teresa , Casadevall Arturo 
Published: January 2012

ABSTRACT

We investigated the outcome of the interaction of
Cryptococcus neoformans
with murine macrophages using laser scanning cytometry (LSC). Previous results in our lab had shown that phagocytosis of
C. neoformans
promoted cell cycle progression. LSC allowed us to simultaneously measure the phagocytic index, macrophage DNA content, and 5-ethynyl-2′-deoxyuridine (EdU) incorporation such that it was possible to study host cell division as a function of phagocytosis. LSC proved to be a robust, reliable, and high-throughput method for quantifying phagocytosis. Phagocytosis of
C. neoformans
promoted cell cycle progression, but infected macrophages were significantly less likely to complete mitosis. Hence, we report a new cytotoxic effect associated with intracellular
C. neoformans
residence that manifested itself in impaired cell cycle completion as a consequence of a block in the G
2
/M stage of the mitotic cell cycle. Cell cycle arrest was not due to increased cell membrane permeability or DNA damage. We investigated alveolar macrophage replication
in vivo
and demonstrated that these cells are capable of low levels of cell division in the presence or absence of
C. neoformans
infection. In summary, we simultaneously studied phagocytosis, the cell cycle state of the host cell and pathogen-mediated cytotoxicity, and our results demonstrate a new cytotoxic effect of
C. neoformans
infection on murine macrophages: fungus-induced cell cycle arrest. Finally, we provide evidence for alveolar macrophage proliferation
in vivo
.
The Interplay between the Escherichia coli Rho Guanine Nucleotide Exchange Factor Effectors and the Mammalian RhoGEF Inhibitor EspH
Authors: Wong Alexander R. C. , Clements Abigail , Raymond Benoit , Crepin Valerie F. , Frankel Gad 
Published: January 2012

ABSTRACT

Rho GTPases are important regulators of many cellular processes. Subversion of Rho GTPases is a common infection strategy employed by many important human pathogens. Enteropathogenic
Escherichia coli
and enterohemorrhagic
Escherichia coli
(EPEC and EHEC) translocate the effector EspH, which inactivates mammalian Rho guanine exchange factors (GEFs), as well as Map, EspT, and EspM2, which, by mimicking mammalian RhoGEFs, activate Rho GTPases. In this study we found that EspH induces focal adhesion disassembly, triggers cell detachment, activates caspase-3, and induces cytotoxicity. EspH-induced cell detachment and caspase-3 activation can be offset by EspT, EspM2, and the
Salmonella
Cdc42/Rac1 GEF effector SopE, which remain active in the presence of EspH. EPEC and EHEC therefore use a novel strategy of controlling Rho GTPase activity by translocating one effector to inactivate mammalian RhoGEFs, replacing them with bacterial RhoGEFs. This study also expands the functional range of bacterial RhoGEFs to include cell adhesion and survival.

IMPORTANCE
Many human pathogens use a type III secretion system to translocate effectors that can functionally be divided into signaling, disabling, and countervirulence effectors. Among the signaling effectors are those that activate Rho GTPases, which play a central role in coordinating actin dynamics. However, many pathogens also translocate effectors with antagonistic or counteractive functions. For example,
Salmonella
translocates SopE and SptP, which sequentially turn Rac1 and Cdc42 on and off. In this paper, we show that enteropathogenic
E. coli
translocates EspH, which inactivates mammalian RhoGEFs and triggers cytotoxicity and at the same time translocates the bacterial RhoGEFs EspM2 and EspT, which are insensitive to EspH, and so neutralizes EspH-induced focal adhesion disassembly, cell detachment, and caspase-3 activation. Our data point to an intriguing infection strategy in which EPEC and EHEC override cellular Rho GTPase signaling by disabling mammalian RhoGEFs and replacing them with with bacterial RhoGEFs that promote cell adhesion and survival.
Epidemiology of, and behavioural risk factors for, sexually transmitted human papillomavirus infection in men and women in Britain
Authors: Johnson Anne M , Mercer Catherine H , Beddows Simon , de Silva Natasha , Desai Sarika , Howell-Jones Rebecca , Carder Caroline , Sonnenberg Pam , Fenton Kevin A , Lowndes Catherine , Soldan Kate 
Published: January 2012

ObjectivesPersistent infection with high-risk sexually transmitted human papillomaviruses (HR-HPVs) can lead to development of cervical and other cancers, while low-risk types (low-risk HPV) may cause genital warts. We explored the epidemiology of different HPV types in men and women and their association with demographic and behavioural variables.MethodsWe analysed data collected for the British National Survey of Sexual Attitudes and Lifestyles, a cross-sectional survey undertaken in 1999–2001. Half of all sexually experienced male and female respondents aged 18–44 years were invited to provide a urine sample. We tested 3123 stored urine samples using an in-house Luminex-based HPV genotyping system.ResultsHPV DNA was detected in 29.0% (95% CI 26.7% to 31.3%) of samples from women and 17.4% (95% CI 15.1% to 19.8%) from men. Any of 13 HR-HPV types was detected in 15.9% (95% CI 14.1% to 17.8%) of women and 9.6% (95% CI 8.0% to 11.6%) of men. HPV types 16/18 were found in 5.5% (95% CI 4.5% to 6.8%) of women and 3.0% (95% CI 2.1% to 4.3%) of men; and types 6/11 in 4.7% (95% CI 1.8% to 5.9%) of women and 2.2% (95% CI 1.5% to 3.1%) of men. In multivariate analysis, HR-HPV was associated with new partner numbers, in women with younger age, single status and partner concurrency, and in men with number of partners without using condom(s) and age at first intercourse.ConclusionsHPV DNA was detectable in urine of a high proportion of the sexually active British population. In both genders, HR-HPV was strongly associated with risky sexual behaviour. The minority of HPV infections were of vaccine types. It is important to monitor HPV prevalence and type distribution following the introduction of vaccination of girls.
Rapid synthesis of homoallylic alcohol from aldehyde with allyltributylstannane under solvent-free conditions
Authors: Bora Pranjal P. , Sema H. Atoholi , Wahlang Barisha , Bez Ghanashyam 
Published: January 2012

A catalytic amount (2 mol %) of phosphotungstic acid (PTA) is sufficient to synthesize homoallylic alcohol in excellent yields from aldehyde with allyltributylstannane upon grinding under solvent-free reaction conditions. Easy handling, very short reaction time, solvent-free reaction conditions, and aqueous workup free isolation protocol may make our method very useful for synthetic chemists.