bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of Body Weight, Ethnicity, Oral Contraceptives, and Pregnancy on the Pharmacokinetics of Azithromycin in Women of Childbearing Age
Authors: Fischer James H. , Sarto Gloria E. , Habibi Mitra , Kilpatrick Sarah J. , Tuomala Ruth E. , Shier Janice M. , Wollett Lori , Fischer Patricia A. , Khorana Kinnari S. , Rodvold Keith A. 
Published: November 2011

ABSTRACTWomen of childbearing age commonly receive azithromycin for the treatment of community-acquired infections, including during pregnancy. This study determined azithromycin pharmacokinetics in pregnant and nonpregnant women and identified covariates contributing to pharmacokinetic variability. Plasma samples were collected by using a sparse-sampling strategy from pregnant women at a gestational age of 12 to 40 weeks and from nonpregnant women of childbearing age receiving oral azithromycin for the treatment of an infection. Pharmacokinetic data from extensive sampling conducted on 12 healthy women were also included. Plasma samples were assayed for azithromycin by high-performance liquid chromatography. Population data were analyzed by nonlinear mixed-effects modeling. The population analysis included 53 pregnant and 25 nonpregnant women. A three-compartment model with first-order absorption and a lag time provided the best fit of the data. Lean body weight, pregnancy, ethnicity, and the coadministration of oral contraceptives were covariates identified as significantly influencing the oral clearance of azithromycin and, except for oral contraceptive use, intercompartmental clearance between the central and second peripheral compartments. No other covariate relationships were identified. Compared to nonpregnant women not receiving oral contraceptives, a 21% to 42% higher dose-adjusted azithromycin area under the plasma concentration-time curve (AUC) occurred in non-African American women who were pregnant or receiving oral contraceptives. Conversely, azithromycin AUCs were similar between pregnant African American women and nonpregnant women not receiving oral contraceptives. Although higher levels of maternal and fetal azithromycin exposure suggest that lower doses be administered to non-African American women during pregnancy, the consideration of azithromycin pharmacodynamics during pregnancy should guide any dose adjustments.
Changes in Ciprofloxacin Resistance Levels in Enterobacter aerogenes Isolates Associated with Variable Expression of the
aac
(
6
′)
-Ib-cr
Gene
Authors: Ruiz Elena , Ocampo-Sosa Alain A. , Alcoba-Flórez Julia , Román Elena , Arlet Guillaume , Torres Carmen , Martínez-Martínez Luis 
Published: November 2011

ABSTRACT

Two closely related
Enterobacter aerogenes
isolates presented a new identical
aac
(
6
′)
-Ib-cr
genetic environment, including IS
26
. One isolate showed lower MICs of ciprofloxacin, norfloxacin, tobramycin, and amikacin and decreased expression of
aac
(
6
′)
-Ib-cr
, which might be related to a 12-bp deletion causing a displacement of the −10 box upstream of the
aac
(
6
′)
-Ib-cr
gene.
Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations
Authors: Else L. J. , Douglas M. , Dickinson L. , Back D. J. , Khoo S. H. , Taylor G. P. 
Published: November 2011

ABSTRACTLopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV-infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC0–12) and maximum concentration were ∼15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy.
Potent Antiviral Activity of Topoisomerase I and II Inhibitors against Kaposi's Sarcoma-Associated Herpesvirus
Authors: González-Molleda Lorenzo , Wang Yan , Yuan Yan 
Published: November 2011

ABSTRACT

The lytic DNA replication of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates at an origin (
ori-Lyt
) and requires
trans
-acting elements, both viral and cellular. We recently demonstrated that several host cellular proteins, including topoisomerases I and II (Topo I and II), are involved in KSHV lytic DNA replication (Y. Wang, H. Li, Q. Tang, G. G. Maul, and Y. Yuan. J. Virol. 82: 2867–2882, 2008). To assess the importance of these topoisomerases in viral lytic replication, shRNA-mediated gene silencing was used. Depletion of Topo I and II severely inhibited viral lytic DNA replication as well as virion production, suggesting essential roles of these cellular proteins in viral DNA replication. The discovery of Topo I and II as enzymes indispensable for KSHV DNA replication raises a possibility that these cellular proteins could be new targets of therapeutic approaches to halt KSHV replication and treat KSHV-associated diseases. In this report, we examined one Topo I inhibitor and several Topo II inhibitors (inclusive of Topo II poison and catalytic inhibitors) as potential therapeutic agents for blocking KSHV replication. The Topo II catalytic inhibitors in general exhibited marked inhibition on KSHV replication and minimal cytotoxicity. In particular, novobiocin, with the best selectivity index (SI = 31.62) among the inhibitors tested in this study, is effective in inhibiting KSHV DNA replication and virion production but shows little adverse effect on cell proliferation and cycle progression in its therapeutic concentration, suggesting its potential to become an effective and safe drug for the treatment of human diseases associated with KSHV infection.
Antibiotic Sensitivity of 40 Mycoplasma pneumoniae Isolates and Molecular Analysis of Macrolide-Resistant Isolates from Beijing, China
Authors: Zhao Fei , Lv Min , Tao Xiaoxia , Huang Hui , Zhang Binghua , Zhang Zhen , Zhang Jianzhong 
Published: November 2011

ABSTRACT

MICs of eight antibiotics were detected with 40 Chinese
Mycoplasma pneumoniae
isolates. Thirty-eight isolates (95%) were macrolide resistant. Each macrolide-resistant isolate harbored an A2063G or A2064G point mutation in the 23S rRNA gene. All 40 isolates (100%) were type I strains, but they might have originated from different clones.
Amino Acid Substitutions at Position 95 in GyrA Can Add Fluoroquinolone Resistance to Mycobacterium leprae
Authors: Yokoyama Kazumasa , Kim Hyun , Mukai Tetsu , Matsuoka Masanori , Nakajima Chie , Suzuki Yasuhiko 
Published: November 2011

ABSTRACTAmino acid substitutions at position 89 or 91 in GyrA of fluoroquinolone-resistantMycobacterium lepraeclinical isolates have been reported. In contrast, those at position 94 inM. tuberculosis, equivalent to position 95 inM. leprae, have been identified most frequently. To verify the possible contribution of amino acid substitutions at position 95 inM. lepraeto fluoroquinolone resistance, we conducted anin vitroassay using wild-type and mutant recombinant DNA gyrases. Fluoroquinolone-mediated supercoiling activity inhibition assay and DNA cleavage assay revealed the potent contribution of an amino acid substitution of Asp to Gly or Asn at position 95 to fluoroquinolone resistance. These results suggested the possible future emergence of quinolone-resistantM. lepraeisolates with these amino acid substitutions and the usefulness of detecting these mutations for the rapid identification of fluoroquinolone resistance in leprosy.
An Inside Job: Hacking into Janus Kinase/Signal Transducer and Activator of Transcription Signaling Cascades by the Intracellular Protozoan Toxoplasma gondii
Authors: Denkers Eric Y. , Bzik David J. , Fox Barbara A. , Butcher Barbara A. 
Published: November 2011

ABSTRACTThe intracellular protozoanToxoplasma gondiiis well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target cell of parasite infection, the injection of ROP16 has multiple consequences, including downregulation of proinflammatory cytokine signaling and macrophage deviation to an alternatively activated phenotype.
Ulinastatin, a Urinary Trypsin Inhibitor, for the Initial Treatment of Patients With Kawasaki Disease
Authors: Kanai Takashi , Ishiwata Takahiro , Kobayashi Tohru , Sato Hiroki , Takizawa Mari , Kawamura Yoichi , Tsujimoto Hiroshi , Nakatani Keigo , Ishibashi Naoko , Nishiyama Mitsunori , Hatai Yoshiho , Asano Yuh , Kobayashi Tomio , Takeshita Seiichiro , Nonoyama Shigeaki 
Published: November 2011

Background—
Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL.

Methods and Results—

We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25–0.86;
P
=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17–0.60;
P
<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38–0.73;
P
<0.001). The adjusted OR was 0.30 (95% CI, 0.20–0.44;
P
<0.001).

Conclusions—
UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.
Modeled and Observed Variations in Storm Divergence and Stratiform Rain Production in Southeastern Texas
Authors: Hopper Larry J. , Schumacher Courtney 
Published: November 2011

Abstract
Storm divergence profiles observed by an S-band Doppler radar are compared to ensemble simulations of 10 disparate precipitating systems occurring in warm-season, weakly baroclinic, and strongly baroclinic environments in southeastern Texas. Eight triply nested mesoscale model simulations are conducted for each case using single- and double-moment microphysics with four convective treatments (i.e., two convective parameterizations and explicit versus parameterized convection at 9 km). Observed and simulated radar reflectivities are objectively separated into convective, stratiform, and nonprecipitating anvil columns and comparisons are made between ensemble mean echo coverages and levels of nondivergence (LNDs). In both the model and observations, storms occurring in less baroclinic environments have more convective rain area, less stratiform rain area, and more elevated divergence profiles.
The model ensemble and observations agree best for well-organized leading-line trailing-stratiform systems. Excessive convective area fractions are simulated for several less-organized cases, especially those whose ensemble mean LNDs are about 1–2 km more elevated than observed. Simulations parameterizing convection on the intermediate grid produced less-elevated divergence profiles with smaller magnitudes compared to their explicit counterparts. In one warm-season case, utilizing double-moment microphysics when parameterizing convection on both outer grids generated lower LNDs associated with variations in convective intensity and depth, detraining less ice to anvil and stratiform regions at midlevels relative to its single-moment counterpart. Similarly, mesoscale convective vortex simulations employing an ensemble-based versus a single-closure convective parameterization on both outer grids produced the least-elevated heating structures (closer to observed), resulting in the weakest midlevel vortices.
Evidence of Bottom-Trapped Currents in the Kuroshio Extension Region
Authors: Bishop Stuart P. , Watts D. Randolph , Park Jae-Hun , Hogg Nelson G. 
Published: November 2011

Abstract
As part of the Kuroshio Extension System Study, observations from five current meter moorings reveal that the abyssal currents are weakly bottom intensified. In the framework of linear quasigeostrophic flow, the best fitted vertical trapping depths range from 8 to 15 km in the absence of steep topography, but one mooring near an isolated seamount exhibited vertical trapping that was more pronounced and energetic with a vertical trapping depth of 5 km. The ratios of current speeds and geostrophic pressure streamfunctions at the sea surface compared to the bottom are 88% in the absence of steep topography, 63% near an isolated seamount, and overall on average 83% of their value at a reference depth of 5300 m. It is hypothesized that weakly depth-dependent eddies impinging upon topographic features introduce to the flow the horizontal length scales of the topography, and these smaller lateral scales are subject to bottom intensification.
Thickness-Weighted Mean Theory for the Effect of Surface Gravity Waves on Mean Flows in the Upper Ocean
Authors: Aiki Hidenori , Greatbatch Richard J. 
Published: November 2011

Abstract
The residual effect of surface gravity waves on mean flows in the upper ocean is investigated using thickness-weighted mean (TWM) theory applied in a vertically Lagrangian and horizontally Eulerian coordinate system. Depth-dependent equations for the conservation of volume, momentum, and energy are derived. These equations allow for (i) finite amplitude fluid motions, (ii) the horizontal divergence of currents, and (iii) a concise treatment of both kinematic and viscous boundary conditions at the sea surface. Under the assumptions of steady and monochromatic waves and a uniform turbulent viscosity, the TWM momentum equations are used to illustrate the pressure- and viscosity-induced momentum fluxes through the surface, which are implicit in previous studies of the wave-induced modification of the classical Ekman spiral problem. The TWM approach clarifies, in particular, the surface momentum flux associated with the so-called virtual wave stress of Longuet-Higgins. Overall, the TWM framework can be regarded as an alternative to the three-dimensional Lagrangian mean framework of Pierson. Moreover, the TWM framework can be used to include the residual effect of surface waves in large-scale circulation models. In specific models that carry the TWM velocity appropriate for advecting tracers as their velocity variable, the turbulent viscosity term should be modified so that the viscosity acts only on the Eulerian mean velocity.
Automation in Surgery
Authors: Manzey Dietrich , Luz Maria , Mueller Stefan , Dietz Andreas , Meixensberger Juergen , Strauss Gero 
Published: November 2011

Objective: Human performance consequences of a new technology of image-guided navigation (IGN) support for surgeons are investigated. Background: Navigated control (NC) represents an advancement of IGN technology. In contrast to currently available pointer-based systems, it represents a higher degree of automation that supports processes not only of information analysis and integration but also of intraoperative decision making. Method: In the first experiment, 14 surgical novices performed a simulated mastoidectomy with and without NC support. Effects of provision of the system were analyzed with respect to different measures of surgical performance and outcome, workload, and situation awareness. In the second experiment, 21 advanced medical students were trained to perform a mastoidectomy by practicing it either with or without NC support. It was investigated to what extent the provision of the system during practice would affect the acquisition of surgical skills. Results: The results reveal that NC support can reduce both the risk of intraoperative injuries and complications as well as the physiological effort of surgeons. “Cost effects” compared to a conventional (i.e., not supported) surgery emerged with respect to the time needed for the surgery, increased subjective workload, reduced spare capacity, and a reduced level of situation awareness. However, no significant effects on processes of skill acquisition were found. Conclusion: NC systems can contribute to improved patient safety. Most of the cost effects seem to be related not to the basic principle of NC but to its current technological implementation. Application: The results have consequences for the design and clinical use of automated navigation support.
A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies
Authors: Allen Kristi L. , Fonseca Fabio V. , Betapudi Venkaiah , Willard Belinda , Zhang Jainwei , McCrae Keith R. 
Published: November 2011

AbstractAntiphospholipid Abs (APLAs) are associated with thrombosis and recurrent fetal loss. These Abs are primarily directed against phospholipid-binding proteins, particularly β2GPI, and activate endothelial cells (ECs) in a β2GPI-dependent manner after binding of β2GPI to EC annexin A2. Because annexin A2 is not a transmembrane protein, the mechanisms of APLA/anti-β2GPI Ab–mediated EC activation are uncertain, although a role for a TLR4/myeloid differentiation factor 88–dependent pathway leading to activation of NF-κB has been proposed. In the present study, we confirm a critical role for TLR4 in anti-β2GPI Ab–mediated EC activation and demonstrate that signaling through TLR4 is mediated through the assembly of a multiprotein signaling complex on the EC surface that includes annexin A2, TLR4, calreticulin, and nucleolin. An essential role for each of these proteins in cell activation is suggested by the fact that inhibiting the expression of each using specific siRNAs blocked EC activation mediated by APLAs/anti-β2GPI Abs. These results provide new evidence for novel protein-protein interactions on ECs that may contribute to EC activation and the pathogenesis of APLA/anti-β2GPI–associated thrombosis and suggest potential new targets for therapeutic intervention in antiphospholipid syndrome.
Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients
Authors: Schönland Stefan O. , Hegenbart Ute , Bochtler Tilmann , Mangatter Anja , Hansberg Marion , Ho Anthony D. , Lohse Peter , Röcken Christoph 
Published: November 2011

AbstractAmyloidoses are characterized by organ deposition of misfolded proteins. This study evaluated immunohistochemistry as a diagnostic tool for the differentiation of amyloid subentities, which is warranted for accurate treatment. A total of 117 patients were systematically investigated by clinical examination, laboratory tests, genotyping, and immunohistochemistry on biopsy specimens. Immunohistochemistry enabled the classification in 94% of the cases. For subsequent analysis, the patient population was divided into 2 groups. The first group included all patients whose diagnosis could be verified by typical clinical signs or an inherited amyloidogenic mutation. In this group, immunohistochemical subtyping was successful in 49 of 51 cases and proved accurate in each of the 49 cases, corresponding to a sensitivity of 96% and a specificity of 100%. The second group included patients with systemic light chain amyloidosis without typical signs, senile transthyretin, or hereditary amyloidosis with a concomitant monoclonal gammopathy. Immunohistochemistry allowed to define the subentities in 61 of 66 (92%) of these cases. Immunohistochemistry performed by a highly specialized pathologist combined with clinical examination and genotyping leads to a high accuracy of amyloidosis classification and is the standard in our center. However, new techniques, such as mass spectroscopy-based proteomics, were recently developed to classify inconclusive cases.
The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax
Authors: Fryrear Kimberly A. , Guo Xin , Kerscher Oliver , Semmes O. John 
Published: November 2011

AbstractThe Really Interesting New Gene (RING) Finger Protein 4 (RNF4) represents a class of ubiquitin ligases that target Small Ubiquitin-like Modifier (SUMO)–modified proteins for ubiquitin modification. To date, the regulatory function of RNF4 appears to be ubiquitin-mediated degradation of sumoylated cellular proteins. In the present study, we show that the Human T-cell Leukemia Virus Type 1 (HTLV-1) oncoprotein Tax is a substrate for RNF4 both in vivo and in vitro. We mapped the RNF4-binding site to a region adjacent to the Tax ubiquitin/SUMO modification sites K280/K284. Interestingly, RNF4 modification of Tax protein results in relocalization of the oncoprotein from the nucleus to the cytoplasm. Overexpression of RNF4, but not the RNF4 RING mutant, resulted in cytoplasmic enrichment of Tax. The RNF4-induced nucleus-to-cytoplasm relocalization was associated with increased NF-κB–mediated and decreased cAMP Response Element-Binding (CREB)–mediated Tax activity. Finally, depletion of RNF4 by RNAi prevented the DNA damage–induced nuclear/cytoplasmic translocation of Tax. These results provide important new insight into STUbL-mediated pathways that regulate the subcellular localization and functional dynamics of viral oncogenes.