bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of caffeine in plasma and saliva, and the influence of caffeine abstinence on CYP1A2 metrics
Authors: Perera Vidya , Gross Annette S , Xu Hongmei , McLachlan Andrew J 
Published: July 2011

Abstract

Objectives
To investigate the utility of metrics of CYP1A2 activity using caffeine as a probe, and saliva and plasma sampling with or without a 24-h caffeine abstinence.

Methods
This was a cross-over pharmacokinetic study in 30 healthy male subjects who received a single oral 100 mg caffeine dose after 24-h caffeine abstinence or after maintaining their regular caffeine intake (no caffeine abstinence). Serial blood and saliva samples were collected simultaneously over 24 h. Caffeine and paraxanthine concentrations were measured using a validated HPLC assay.

Key findings
There was a strong correlation between the paraxanthine/caffeine AUC0–24 ratio (reference metric) and the paraxanthine/caffeine concentration (Ct) ratio at 4 h (C4) in both saliva and plasma (r ≥ 0.75). The paraxanthine/caffeine AUC0–24 ratio in plasma and saliva did not differ between the 24-h caffeine abstinence and the no abstinence period (P &gt; 0.05). The optimal paraxanthine/caffeine Ct that correlated with the plasma paraxanthine/caffeine AUC0–24 ratio in the 24-h abstinence period was 2 and 4 h (r = 0.88) in plasma, and 4 and 6 h in saliva (r = 0.70), while it was the saliva 4 h time-point in the no abstinence period (r = 0.78).

Conclusions
The saliva paraxanthine/caffeine concentration ratio at 4 h was a suitable metric to assess CYP1A2 activity after oral administration of caffeine without the need for 24-h caffeine abstinence.
New empirical evidence of the validity of the Chronic Pain Acceptance Questionnaire: The differential influence of activity engagement and pain willingness on adjustment to chronic pain
Authors: Bendayan Rebecca , Esteve Rosa , Blanca María J. 
Published: July 2011

Objective. The aims of this study were to examine the internal structure of the Spanish version of the Chronic Pain Acceptance Questionnaire and present new empirical evidence regarding its validity.Design and Methods. A sample of 315 chronic pain patients attending a pain clinic completed a battery of instruments to assess pain acceptance, general psychological acceptance, depression, anxiety, pain intensity, functional impairment, and current functioning.Results. Confirmatory factor analysis supported the validity of a 20‐item version with two subscales corresponding to two independent factors: Activity Engagement and Pain Willingness. Structural Equation Modelling showed that the association between pain intensity and anxiety and depression was fully mediated by Activity Engagement which partially mediated the association between pain intensity and functioning. Pain Willingness partially mediated the influence of pain intensity on functional impairment.Conclusions. These findings indicate the differential influence of both components on adjustment to chronic pain.
Transition to Turbulence in Accelerating Pipe Flow
Authors: Annus Ivar , Koppel Tiit 
Published: July 2011

Abstract
A uniformly accelerated laminar flow in a pipe, initially at rest, is analyzed. The acceleration increases the critical Reynolds number remarkably. New experimental findings are used to describe the transitional process in accelerating pipe flow. The results are shown to validate the previously suggested transition parameters obtained on the basis of results on small diameter pipes. The influence of the transition process on mean values is studied. The relationships between flow parameters and transition time were derived from the experimental results for data available. The time from the start of the flow to the initiation of turbulence can be predicted by an empirical formula.
Novel Genotyping and Quantitative Analysis of Neuraminidase Inhibitor Resistance-Associated Mutations in Influenza A Viruses by Single-Nucleotide Polymorphism Analysis
Authors: Duan Susu , Boltz David A. , Li Jiang , Oshansky Christine M. , Marjuki Henju , Barman Subrata , Webby Richard J. , Webster Robert G. , Govorkova Elena A. 
Published: July 2011

ABSTRACTNeuraminidase (NA) inhibitors are among the first line of defense against influenza virus infection. With the increased worldwide use of the drugs, antiviral susceptibility surveillance is increasingly important for effective clinical management and for public health epidemiology. Effective monitoring requires effective resistance detection methods. We have developed and validated a novel genotyping method for rapid detection of established NA inhibitor resistance markers in influenza viruses by single nucleotide polymorphism (SNP) analysis. The multi- or monoplex SNP analysis based on single nucleotide extension assays was developed to detect NA mutations H275Y and I223R/V in pandemic H1N1 viruses, H275Y in seasonal H1N1 viruses, E119V and R292K in seasonal H3N2 viruses, and H275Y and N295S in H5N1 viruses. The SNP analysis demonstrated high sensitivity for low-content NA amplicons (0.1 to 1 ng/μl) and showed 100% accordant results against a panel of defined clinical isolates. The monoplex assays for the H275Y NA mutation allowed precise and accurate quantification of the proportions of wild-type and mutant genotypes in virus mixtures (5% to 10% discrimination), with results comparable to those of pyrosequencing. The SNP analysis revealed the lower growth fitness of an H275Y mutant compared to the wild-type pandemic H1N1 virus by quantitatively genotyping progeny viruses grown in normal human bronchial epithelial cells. This novel method offers high-throughput screening capacity, relatively low costs, and the wide availability of the necessary equipment, and thus it could provide a much-needed approach for genotypic screening of NA inhibitor resistance in influenza viruses.
A Translation Inhibitor That Suppresses Dengue Virus
In Vitro
and
In Vivo
Authors: Wang Qing-Yin , Kondreddi Ravinder Reddy , Xie Xuping , Rao Ranga , Nilar Shahul , Xu Hao Ying , Qing Min , Chang David , Dong Hongping , Yokokawa Fumiaki , Lakshminarayana Suresh B. , Goh Anne , Schul Wouter , Kramer Laura , Keller Thomas H. , Shi Pei-Yong 
Published: July 2011

ABSTRACT

We describe a novel translation inhibitor that has anti-dengue virus (DENV) activity
in vitro
and
in vivo
. The inhibitor was identified through a high-throughput screening using a DENV infection assay. The compound contains a benzomorphan core structure. Mode-of-action analysis indicated that the compound inhibits protein translation in a viral RNA sequence-independent manner. Analysis of the stereochemistry demonstrated that only one enantiomer of the racemic compound inhibits viral RNA translation. Medicinal chemistry was performed to eliminate a metabolically labile glucuronidation site of the compound to improve its
in vivo
stability. Pharmacokinetic analysis showed that upon a single subcutaneous dosing of 25 mg/kg of body weight in mice, plasma levels of the compound reached a
C
max
(maximum plasma drug concentration) above the protein-binding-adjusted 90% effective concentration (EC
90
) value of 0.96 μM. In agreement with the
in vivo
pharmacokinetic results, treatment of DENV-infected mice with 25 mg/kg of compound once per day reduced peak viremia by about 40-fold. However, mice treated with 75 mg/kg of compound per day exhibited adverse effects. Collectively, our results demonstrate that the benzomorphan compounds inhibit DENV through suppression of RNA translation. The therapeutic window of the current compounds needs to be improved for further development.
Helicobacter pylori Eradication by Sitafloxacin-Lansoprazole Combination and Sitafloxacin Pharmacokinetics in Mongolian Gerbils and ItsIn VitroActivity and Resistance Development
Authors: Yamamoto Tatsuo , Takano Tomomi , Higuchi Wataru , Nishiyama Akihito , Taneike Ikue , Yoshida Kumi , Kanda Hiroko , Imamura Yuichiro 
Published: July 2011

ABSTRACTA total of 293 strains ofHelicobacter pylori, including strains resistant to levofloxacin, clarithromycin, metronidazole, or amoxicillin, were examined forin vitrosusceptibility to 10 antimicrobial agents. Among these agents, sitafloxacin (a fluoroquinolone) showed the greatest activity (MIC90, 0.06 μg/ml), with high bactericidal activity and synergy in sitafloxacin-lansoprazole (a proton pump inhibitor) combination. In a Mongolian gerbil model with aH. pyloriATCC 43504 challenge, marked eradication effects were observed at ≥1 mg/kg for sitafloxacin, ≥10 mg/kg for levofloxacin, and ≥10 mg/kg for lansoprazole, reflecting MIC levels for each agent (0.008, 0.25, and 2 μg/ml, respectively). The therapeutic rates were 83.3% for the sitafloxacin (0.3 mg/kg)-lansoprazole (2.5 mg/kg) combination and 0% for either sitafloxacin or lansoprazole alone. The maximum serum concentration (Cmax) of sitafloxacin was 0.080 ± 0.054 μg/ml at 30 min, when orally administered at 1 mg/kg. The simultaneous administration of lansoprazole resulted in no difference. In the resistance development assay, MICs of levofloxacin increased 64- to 256-fold withgyrAmutations (Ala88Pro and Asn87Lys), while MICs of sitafloxacin only up to 16-fold with the Asn87Lys mutation. The data suggest that sitafloxacin exhibited superior anti-H. pyloriactivity with low rates of resistance developmentin vitroand that, reflecting highin vitroactivities, sitafloxacin-lansoprazole combination exhibited strong therapeutic effects in Mongolian gerbils with aCmaxof sitafloxacin that was 10-fold higher than the MIC value at a 1-mg/kg administration.
Ex Vivo
Drug Susceptibility of Ferroquine against Chloroquine-Resistant Isolates of Plasmodium falciparum and P. vivax
Authors: Marfurt Jutta , Chalfein Ferryanto , Prayoga Pak , Wabiser Frans , Kenangalem Enny , Piera Kim A. , MacHunter Barbara , Tjitra Emiliana , Anstey Nicholas M. , Price Ric N. 
Published: July 2011

ABSTRACT

Ferroquine (FQ; SSR97193), a ferrocene-containing 4-aminoquinoline derivate, has potent
in vitro
efficacy against chloroquine (CQ)-resistant
Plasmodium falciparum
and CQ-sensitive
P. vivax
. In the current study,
ex vivo
FQ activity was tested in multidrug-resistant
P. falciparum
and
P. vivax
field isolates using a schizont maturation assay. Although FQ showed excellent activity against CQ-sensitive and -resistant
P. falciparum
and
P. vivax
(median 50% inhibitory concentrations [IC
50
s], 9.6 nM and 18.8 nM, respectively), there was significant cross-susceptibility with the quinoline-based drugs chloroquine, amodiaquine, and piperaquine (for
P. falciparum
,
r
= 0.546 to 0.700,
P
< 0.001; for
P. vivax
,
r
= 0.677 to 0.821,
P
< 0.001). The observed
ex vivo
cross-susceptibility is likely to reflect similar mechanisms of drug uptake/efflux and modes of drug action of this drug class. However, the potent activity of FQ against resistant isolates of both
P. falciparum
and
P. vivax
highlights a promising role for FQ as a lead antimalarial against CQ-resistant
Plasmodium
and a useful partner drug for artemisinin-based combination therapy.
Pathogenesis and Pathophysiology of Pneumococcal Meningitis
Authors: Mook-Kanamori Barry B. , Geldhoff Madelijn , van der Poll Tom , van de Beek Diederik 
Published: July 2011

SUMMARYPneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization byStreptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.
Randomized Trial of the Immunogenicity and Safety of the Hepatitis B Vaccine Given in an Accelerated Schedule Coadministered with the Human Papillomavirus Type 16/18 AS04-Adjuvanted Cervical Cancer Vaccine
Authors: Leroux-Roels Geert , Haelterman Edwige , Maes Cathy , Levy Jack , De Boever Fien , Licini Laurent , David Marie-Pierre , Dobbelaere Kurt , Descamps Dominique 
Published: July 2011

ABSTRACT

The human papillomavirus type 16/18 (HPV-16/18) AS04-adjuvanted cervical cancer vaccine is licensed for females aged 10 years and above and is therefore likely to be coadministered with other licensed vaccines, such as hepatitis B. In this randomized, open-label study, we compared the immunogenicity of the hepatitis B vaccine administered alone (HepB group) or with the HPV-16/18 AS04-adjuvanted vaccine (HepB+HPV group) in healthy women aged 20 to 25 years (clinical trial NCT00637195). The hepatitis B vaccine was given at 0, 1, 2, and 12 months (an accelerated schedule which may be required by women at high risk), and the HPV-16/18 vaccine was given at 0, 1, and 6 months. One month after the third dose of hepatitis B vaccine, in the according-to-protocol cohort (
n
= 72 HepB+HPV;
n
= 76 HepB), hepatitis B seroprotection rates (titer of ≥10 mIU/ml) were 96.4% (95% confidence interval [CI], 87.5 to 99.6) and 96.9% (CI, 89.2 to 99.6) in the HepB+HPV and HepB groups, respectively, in women initially seronegative for anti-hepatitis B surface antigen (HBs) and anti-hepatitis B core antigen (HBc). Corresponding geometric mean titers of anti-HBs antibodies were 60.2 mIU/ml (CI, 40.0 to 90.5) and 71.3 mIU/ml (CI, 53.9 to 94.3). Anti-HBs antibody titers rose substantially after the fourth dose of hepatitis B vaccine. All women initially seronegative for anti-HPV-16 and anti-HPV-18 antibodies seroconverted after the second HPV-16/18 vaccine dose and remained seropositive up to 1 month after the third dose. Both vaccines were generally well tolerated, with no difference in reactogenicity between groups. In conclusion, coadministration of the HPV-16/18 AS04-adjuvanted vaccine did not affect the immunogenicity or safety of the hepatitis B vaccine administered in an accelerated schedule in young women.
Long-Term Humoral and Cellular Immune Responses Elicited by a Heterologous Plasmodium vivax Apical Membrane Antigen 1 Protein Prime/Adenovirus Boost Immunization Protocol
Authors: Bouillet Leoneide Érica Maduro , Dias Mariana Oliveira , Dorigo Natália Alves , Moura Andrew Douglas , Russell Bruce , Nosten Francois , Renia Laurent , Braga Érika Martins , Gazzinelli Ricardo Tostes , Rodrigues Maurício M. , Soares Irene S. , Bruna-Romero Oscar 
Published: July 2011

ABSTRACTApical membrane antigen 1 (AMA-1) is an invasion-relatedPlasmodiumantigen that is expressed during both intracellular and extracellular asexual stages of the parasite's life cycle, making it an ideal target for induction of humoral and cellular immune responses that can protect against malaria. We show here that when it is administered as a recombinant protein (P) in Montanide ISA720 adjuvant, followed by a recombinant human type 5 adenovirus (Ad), intense and long-lastingPlasmodium vivaxAMA-1-specific antibody responses (including both IgG1 and IgG2a), as well as proliferative memory T cell responses, can be detected in immunized mice. Memory T cells displayed both central (CD44hiCD62Lhi) and effector (CD44hiCD62Llo) phenotypes, with the central memory phenotype prevailing (56% of AMA-1-specific proliferating cells). Considering the main traits of the memory immune responses induced against AMA-1, this particular sequence of immunogens (P followed by Ad), but no others (Ad/Ad, Ad/P, or P/P), displayed an optimal synergistic effect. These results give further support to the need for preclinical studies ofP. vivaxvaccine candidate AMA-1 administered in prime/boost protocols that include recombinant proteins and adenoviral vectors.
Potential Role of Fibroblast-Like Synoviocytes in Joint Damage Induced by Brucella abortus Infection through Production and Induction of Matrix Metalloproteinases
Authors: Scian Romina , Barrionuevo Paula , Giambartolomei Guillermo H. , De Simone Emilio A. , Vanzulli Silvia I. , Fossati Carlos A. , Baldi Pablo C. , Delpino M. Victoria 
Published: July 2011

ABSTRACTArthritis is one of the most common complications of human brucellosis, but its pathogenic mechanisms have not been elucidated. Fibroblast-like synoviocytes (FLS) are known to be central mediators of joint damage in inflammatory arthritides through the production of matrix metalloproteinases (MMPs) that degrade collagen and of cytokines and chemokines that mediate the recruitment and activation of leukocytes. In this study we show thatBrucella abortusinfects and replicates in human FLS (SW982 cell line)in vitroand that infection results in the production of MMP-2 and proinflammatory mediators (interleukin-6 [IL-6], IL-8, monocyte chemotactic protein 1 [MCP-1], and granulocyte-macrophage colony-stimulating factor [GM-CSF]). Culture supernatants fromBrucella-infected FLS induced the migration of monocytes and neutrophilsin vitroand also induced these cells to secrete MMP-9 in a GM-CSF- and IL-6-dependent fashion, respectively. Reciprocally, culture supernatants fromBrucella-infected monocytes and neutrophils induced FLS to produce MMP-2 in a tumor necrosis factor alpha (TNF-α)-dependent fashion. The secretion of proinflammatory mediators and MMP-2 by FLS did not depend on bacterial viability, since it was also induced by heat-killedB. abortus(HKBA) and by a modelBrucellalipoprotein (L-Omp19). These responses were mediated by the recognition ofB. abortusantigens through Toll-like receptor 2. The intra-articular injection of HKBA or L-Omp19 into the knee joint of mice resulted in the local induction of the proinflammatory mediators MMP-2 and MMP-9 and in the generation of a mixed inflammatory infiltrate. These results suggest that FLS, and phagocytes recruited by them to the infection focus, may be involved in joint damage during brucellar arthritis through the production of MMPs and proinflammatory mediators.
The Papillomavirus E1 Helicase Activates a Cellular DNA Damage Response in Viral Replication Foci
Authors: Sakakibara Nozomi , Mitra Ruchira , McBride Alison A. 
Published: July 2011

ABSTRACT
The papillomavirus E1 and E2 proteins are essential for viral genome replication. E1 is a helicase that unwinds the viral origin and recruits host cellular factors to replicate the viral genome. E2 is a transcriptional regulator that helps recruit the E1 helicase to the origin and also plays a role in genome partitioning. We find that when coexpressed, the E1 and E2 proteins from several papillomavirus types localize to defined nuclear foci and result in growth suppression of the host cells. Growth suppression was due primarily to E1 protein function, and nuclear expression of E1 was accompanied by activation of a DNA damage response, resulting in phosphorylation of ATM, Chk2, and H2AX. Growth suppression and ATM activation required the ATPase and origin-specific binding functions of the E1 protein and resulted in active DNA repair, as evidenced by incorporation of nucleotide analogs and detection of free DNA ends. In the presence of the E2 protein, these activities became localized to nuclear foci. We postulate that these foci represent viral replication factories and that a cellular DNA damage response is activated to facilitate replication of viral DNA.
HIV-Specific Functional Antibody Responses in Breast Milk Mirror Those in Plasma and Are Primarily Mediated by IgG Antibodies
Authors: Fouda Genevieve G. , Yates Nicole L. , Pollara Justin , Shen Xiaoying , Overman Glenn R. , Mahlokozera Tatenda , Wilks Andrew B. , Kang Helen H. , Salazar-Gonzalez Jesus F. , Salazar Maria G. , Kalilani Linda , Meshnick Steve R. , Hahn Beatrice H. , Shaw George M. , Lovingood Rachel V. , Denny Thomas N. , Haynes Barton , Letvin Norman L. , Ferrari Guido , Montefiori David C. , Tomaras Georgia D. , Permar Sallie R. ,   the Center for HIV/AIDS Vaccine Immunology
Published: July 2011

ABSTRACT

Despite months of mucosal virus exposure, the majority of breastfed infants born to HIV-infected mothers do not become infected, raising the possibility that immune factors in milk inhibit mucosal transmission of HIV. HIV Envelope (Env)-specific antibodies are present in the milk of HIV-infected mothers, but little is known about their virus-specific functions. In this study, HIV Env-specific antibody binding, autologous and heterologous virus neutralization, and antibody-dependent cell cytotoxicity (ADCC) responses were measured in the milk and plasma of 41 HIV-infected lactating women. Although IgA is the predominant antibody isotype in milk, HIV Env-specific IgG responses were higher in magnitude than HIV Env-specific IgA responses in milk. The concentrations of anti-HIV gp120 IgG in milk and plasma were directly correlated (
r
= 0.75;
P
< 0.0001), yet the response in milk was 2 logarithm units lower than in plasma. Similarly, heterologous virus neutralization (
r
= 0.39;
P
= 0.010) and ADCC activity (
r
= 0.64;
P
< 0.0001) in milk were directly correlated with that in the systemic compartment but were 2 log units lower in magnitude. Autologous neutralization was rarely detected in milk. Milk heterologous virus neutralization titers correlated with HIV gp120 Env-binding IgG responses but not with IgA responses (
r
= 0.71 and
P
< 0.0001, and
r
= 0.17 and
P
= 0.30). Moreover, IgGs purified from milk and plasma had equal neutralizing potencies against a tier 1 virus (
r
= 0.65;
P
< 0.0001), whereas only 1 out of 35 tested non-IgG milk fractions had detectable neutralization. These results suggest that plasma-derived IgG antibodies mediate the majority of the low-level HIV neutralization and ADCC activity in breast milk.