bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetics of Busulfan in Children: Increased Evidence for Body Surface Area and Allometric Body Weight Dosing of Busulfan in Children
Authors: Trame Mirjam N. , Bergstrand Martin , Karlsson Mats O. , Boos Joachim , Hempel Georg 
Published: September 2011

Abstract
Purpose: To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM.
Experimental Design: The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area (BSA) or allometric body weight (BW) as covariate on clearance (CL) and BW as covariate on volume of distribution (V) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V.
Results: CL values in the present study did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation, we were able to confirm these findings. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 μM*min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation.
Conclusion: We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment. Clin Cancer Res; 17(21); 6867–77. ©2011 AACR.
A Novel Anti-Human HB-EGF Monoclonal Antibody with Multiple Antitumor Mechanisms against Ovarian Cancer Cells
Authors: Miyamoto Shingo , Iwamoto Ryo , Furuya Akiko , Takahashi Kumiko , Sasaki Yuka , Ando Hiroshi , Yotsumoto Fusanori , Yoneda Tomoko , Hamaoka Miki , Yagi Hiroshi , Murakami Takuya , Hori Sayaka , Shitara Kenya , Mekada Eisuke 
Published: September 2011

Abstract
Purpose: Heparin-binding epidermal growth factor (EGF)–like growth factor (HB-EGF) is a member of the EGF family and plays a pivotal role in tumor progression in ovarian cancer. We developed an anti-HB-EGF monoclonal antibody (mAb) and investigated its antitumor activities in vitro and in vivo to evaluate its potential as a therapeutic antibody against ovarian cancer.
Experimental Design: We prepared mAbs from HB-EGF null mice immunized with recombinant human soluble HB-EGF and evaluated their binding and neutralizing activity against HB-EGF. Next, we generated a mouse–human chimeric antibody and examined its in vitro and in vivo antitumor activities.
Results: Two murine anti-HB-EGF mAbs were developed, and one of them, KM3566, was revealed to have a high binding reactivity for membrane-anchored HB-EGF (pro-HB-EGF) expressed on the cell surface, as well as neutralizing activity against growth promoting activity of soluble HB-EGF. The mouse–human chimeric counterpart for KM3566 (cKM3566) induced dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against cancer cells expressing HB-EGF in vitro, and significantly inhibited tumor growth in severe combined immunodeficient mice inoculated with MCAS or ES-2 human ovarian cancer cells.
Conclusions: A novel anti-HB-EGF chimeric antibody, cKM3566, with two antitumor mechanisms, neutralization and ADCC, exhibits potent in vivo antitumor activity. These results indicate that cKM3566 is a promising antiovarian cancer therapeutic antibody. Clin Cancer Res; 17(21); 6733–41. ©2011 AACR.
Assessment of Diffuse Myocardial Fibrosis in Rats Using Small-Animal Look-Locker Inversion Recovery T1 Mapping
Authors: Messroghli Daniel R. , Nordmeyer Sarah , Dietrich Thore , Dirsch Olaf , Kaschina Elena , Savvatis Kostas , O h-Ici Darach , Klein Christoph , Berger Felix , Kuehne Titus 
Published: September 2011

Background—
The concentration of gadopentetate dimeglumine in myocardium and blood can be assessed from T1 measurements and can be used to calculate the extracellular volume (ECV) of the myocardium. We hypothesized that diffuse myocardial fibrosis in a small-animal model could be quantitatively assessed by measuring myocardial ECV using small-animal Look-Locker inversion recovery T1 mapping.

Methods and Results—

Sprague-Dawley rats (n=10) were subjected to continuous angiotensin-2 (AT2) infusion for 2 weeks via a subcutaneously implanted minipump system. Magnetic resonance imaging (MRI) was performed both before and after AT2 infusion. The MRI protocol included multislice cine imaging and before-and-after contrast small-animal Look-Locker inversion recovery T1 mapping and late gadolinium enhancement imaging. Myocardial ECV was calculated from hematocrit and T1 values of blood and myocardium. During the course of AT2 infusion, the mean±SD systolic blood pressure increased from 122±10.9 to 152±27.5 mm Hg (
P
=0.003). Normalized heart weight was significantly higher in AT2-treated animals than in control littermates (
P
=0.033). Cine MRI documented concentric left ventricular hypertrophy. Postcontrast myocardial T1 times were shortened after treatment (median [interquartile range], 712 [63] versus 820 [131] ms;
P
=0.002). Myocardial ECV increased from 17.2% (4.3%) before to 23.0% (6.2%) after AT2 treatment (
P
=0.031), which was accompanied by perivascular fibrosis and microscarring on myocardial histological analysis. There was a moderate level of correlation between ECV and collagen volume fraction, as assessed by histological analysis (
r
=0.69,
P
=0.013).

Conclusions—
In a small-animal model of left ventricular hypertrophy, contrast-enhanced T1 mapping can be used to detect diffuse myocardial fibrosis by quantification of myocardial ECV.
Large-Scale Rossby Normal Modes during Some Recent Northern Hemisphere Winters
Authors: Sassi F. , Garcia R. R. , Hoppel K. W. 
Published: September 2011

Abstract
Large-scale Rossby normal modes are studied for the Northern Hemisphere winters of 2005, 2006, 2008, and 2009 using global observational meteorological analyses spanning the 0–92-km altitude range. Spectral analysis of geopotential height fields shows pronounced peaks at westward-propagating zonal wavenumber 1 near the theoretical locations of the free Rossby waves at 25, 16, 10, and 5 days that, in some cases, have amplitudes significantly larger than the estimated background spectrum. Evidence is also found for a wavenumber-2 free mode near 4 days. A coherence analysis is used to extract the amplitude and phase of the waves, and to isolate those regions of the latitude/altitude plane where the signals are statistically significant. Although the spectral location, temporal evolution, and vertical structure of several of these waves are suggestive of the presence of Rossby normal modes, this study shows that in the real atmosphere the waves only occasionally have the global properties of classical normal modes. Moreover, no evidence is found that the amplitudes of these modes are enhanced during stratospheric sudden warmings.
Effects of Sea-Salt Aerosols on Precipitation in Simulations of Shallow Cumulus
Authors: Kogan Yefim L. , Mechem David B. , Choi Kityan 
Published: September 2011

AbstractA suite of large-eddy simulations with size-resolving microphysical processes was performed in order to assess effects of sea-salt aerosols on precipitation process in trade cumulus. Simulations based on observations from the Rain in Cumulus over the Ocean (RICO) field campaign explored the effects of adding sea-salt nuclei in different size ranges by following the evolution of 369 cloud cells over the 24-h simulation period. The addition of large (small) sea-salt nuclei tends to accelerate (suppress) precipitation formation; however, in marine environments the sea-salt spectra always include a combination of both small (film) and large (jet) nuclei. When realistic sea-salt spectra are specified as a function of surface wind, the effect of the larger nuclei to enhance the precipitation predominates, and accumulated precipitation increases with wind speed. This effect, however, is strongly influenced by the choice of background CCN spectrum. Adding the same sea-salt specification to an environment with a higher background aerosol load results in a decrease in accumulated precipitation with increasing surface wind speed.Results also suggest that the slope of the relationship between vertical velocity W and the concentration of embryonic precipitation particles at cloud base Nr may indicate the role of sea-salt nuclei. A negative slope (Nr decreasing with increasing W) points to the predominance of small sea-salt nuclei, in which larger updrafts activate a greater number of smaller cloud drops with smaller coalescence efficiencies, resulting in fewer embryonic rain drops. A positive slope, on the other hand, indicates the presence of large sea-salt nuclei, which are the source of embryonic rain drops.
Numerical Prediction of Submesoscale Flow in the Nocturnal Stable Boundary Layer over Complex Terrain
Authors: Seaman Nelson L. , Gaudet Brian J. , Stauffer David R. , Mahrt Larry , Richardson Scott J. , Zielonka Jeffrey R. , Wyngaard John C. 
Published: September 2011

Abstract
Numerical weather prediction models often perform poorly for weakly forced, highly variable winds in nocturnal stable boundary layers (SBLs). When used as input to air-quality and dispersion models, these wind errors can lead to large errors in subsequent plume forecasts. Finer grid resolution and improved model numerics and physics can help reduce these errors. The Advanced Research Weather Research and Forecasting model (ARW-WRF) has higher-order numerics that may improve predictions of finescale winds (scales &lt;~20 km) in nocturnal SBLs. However, better understanding of the physics controlling SBL flow is needed to take optimal advantage of advanced modeling capabilities.
To facilitate ARW-WRF evaluations, a small network of instrumented towers was deployed in the ridge-and-valley topography of central Pennsylvania (PA). Time series of local observations and model forecasts on 1.333- and 0.444-km grids were filtered to isolate deterministic lower-frequency wind components. The time-filtered SBL winds have substantially reduced root-mean-square errors and biases, compared to raw data. Subkilometer horizontal and very fine vertical resolutions are found to be important for reducing model speed and direction errors. Nonturbulent fluctuations in unfiltered, very finescale winds, parts of which may be resolvable by ARW-WRF, are shown to generate horizontal meandering in stable weakly forced conditions. These submesoscale motions include gravity waves, primarily horizontal 2D motions, and other complex signatures. Vertical structure and low-level biases of SBL variables are shown to be sensitive to parameter settings defining minimum “background” mixing in very stable conditions in two representative turbulence schemes.
Determinants of child immunization in Nepal: The role of women’s empowerment
Authors: Pandey Shanta , Lee Hae nim 
Published: September 2011

Background: Approximately 1.4 million or 13% of all children who die each year could be prevented with widely-available vaccines. Objective: We examined if women’s empowerment improved child immunization using data on 1,056 mothers with young children from Nepal. Methods: The study utilized the 2006 Nepal Demographic and Health Survey, a nationally-representative sample of 10,793 women from 8,707 households across Nepal. We selected all mothers with first child between the ages of 12 and 23 months at the time of interview. This resulted in a sample of 1,056 mothers. Results: Among the measures of women’s empowerment, mothers’ education was significantly associated with child immunization. The odds of being fully immunized for children of mothers with secondary education were 5.91 times the odds for children of mothers without any formal education. Other measures of women’s empowerment – women’s age at birth of first child, gap in age between spouses, women’s knowledge about sexually-transmitted diseases, their role in intra-household financial, health and mobility decisions, and their perceptions toward wife beating – were not associated with child immunization. Among control variables, mothers who received antenatal care were 3.31 times as likely to immunize their children as mothers who did not receive any antenatal care. Other such barriers to health service use such as cost of care, distance to health services, and quality of health services were not significant. Conclusions: To improve child immunization, Nepal should strengthen its antenatal care services. Additionally, over 56% of mothers in Nepal had no formal education; to improve child health in the long run, the country should focus on education of women and girls.
Procedural Instructions, Principles, and Examples
Authors: Eiriksdottir Elsa , Catrambone Richard 
Published: September 2011

Objective: The goal of this article is to investigate how instructions can be constructed to enhance performance and learning of procedural tasks. Background: Important determinants of the effectiveness of instructions are type of instructions (procedural information, principles, and examples) and pedagogical goal (initial performance, learning, and transfer). Method: Procedural instructions describe how to complete tasks in a stepwise manner, principles describe rules governing the tasks, and examples demonstrate how instances of the task are carried out. The authors review the research literature associated with each type of instruction to identify factors determining effectiveness for different pedagogical goals. Results: The results suggest a trade-off between usability and learnability. Specific instructions help initial performance, whereas more general instructions, requiring problem solving, help learning and transfer. Learning from instructions takes cognitive effort, and research suggests that learners typically opt for low effort. However, it is possible to meet both goals of good initial performance and learning with methods such as fading and by combining different types of instructions. Conclusion: How instructions are constructed influences their effectiveness for the goals of good initial performance, learning, and transfer, and it is therefore important for researchers and practitioners alike to define the pedagogical goal of instructions. Application: If the goal is good initial performance, then instructions should highly resemble the task at hand (e.g., in the form of detailed procedural instructions and examples), but if the goal is good learning and transfer, then instructions should be more abstract, inducing learners to expend the necessary cognitive effort for learning.
Degeneration of the Knee Joint in Skeletally Immature Patients With a Diagnosis of an Anterior Cruciate Ligament Tear
Authors: Lawrence J. Todd R. , Argawal Nina , Ganley Theodore J. 
Published: September 2011

Background: In skeletally immature patients with an anterior cruciate ligament (ACL) tear and significant growth remaining, the risk of inducing a growth disturbance with early reconstruction must be balanced against the risk of further intra-articular damage by delaying treatment until closer to skeletal maturity. Hypothesis: Increased time from injury to ACL reconstruction in children ≤14 years of age will be associated with increased meniscal and chondral injuries at the time of reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: With institutional review board approval, the records of a consecutive series of patients 14 years of age and younger who underwent ACL reconstruction between 1991 and 2005 were reviewed. Demographic, magnetic resonance imaging (MRI), and intraoperative findings were analyzed. Meniscal and articular cartilage injuries were graded. Logistic regression models using both univariable and multivariable regression procedures were used to identify factors independently associated with intra-articular lesions. Fisher exact test and Kaplan-Meier analysis were used to test for differences in intra-articular injuries by time from injury to surgery. Results: Seventy patients were identified. Twenty-nine patients (41%) underwent reconstruction more than 12 weeks from the time of injury. Logistic regression analysis revealed time to surgical reconstruction (odds ratio, 4.1) and a history of a sense of knee instability (odds ratio, 11.4) to be independently associated with medial meniscal tears. Time to surgical reconstruction was also independently associated with medial and lateral compartment chondral injuries (odds ratios, 5.6 and 11.3, respectively). Testing time as a continuous variable, survivorship analysis also confirmed a significant association of time to reconstruction with medial meniscal injury as well as lateral and patellotrochlear cartilage injuries. When present, a delay in treatment of over 12 weeks (29 patients) was associated with an increase in the severity of medial meniscal tears ( P = .011) and higher grade lateral and patellotrochlear chondral injuries ( P = .0014 and P = .038, respectively). Conclusion: Young patients who underwent surgical reconstruction of an acute ACL tear >12 weeks after the injury were noted to have a significant increase in irreparable medial meniscal tears and lateral compartment chondral injuries at the time of reconstruction. When a subjective sense of knee instability was present, this association was even stronger.
Examining Neuromuscular Control During Landings on a Supinating Platform in Persons With and Without Ankle Instability
Authors: Gutierrez Gregory M. , Knight Christopher A. , Swanik Charles B. , Royer Todd , Manal Kurt , Caulfield Brian , Kaminski Thomas W. 
Published: September 2011

Background: Ankle instability is a costly public health concern because of the associated recurrent sprains. It is evident there are neuromuscular control deficits predisposing these individuals to their ankle “giving way.” Individuals with a history of lateral ankle sprain, who did not develop instability, may hold the key to understanding proper neuromuscular control after injury. Hypotheses: On the basis of previous research, the authors hypothesized that individuals with ankle instability would demonstrate reduced peroneal activation, causing a more inverted position of the ankle, before and after landing. Study Design: Controlled laboratory study. Methods: This study aimed to evaluate preparatory and reactive neuromuscular control when landing on a custom-designed ankle supinating device in individuals with ankle instability (AI), individuals with a history of lateral ankle sprains without instability (LAS), and uninjured controls (CON). Forty-five participants (15 per group) were asked to land on a device built to simulate the mechanism of a lateral ankle sprain (supination) while kinematics and muscle activity of the lower extremity were monitored. Results: Contrary to our hypotheses, the AI group displayed significantly increased preparatory ( P = .01) and reactive ( P = .02) peroneal activation, while the LAS group demonstrated a trend toward increased preparatory tibialis anterior muscle activation ( P = .07), leading to a decreased plantar flexion of the ankle at landing. Conclusion: The AI group was likely acting in a protective fashion to a potentially injurious situation, indicating these individuals can activate the peroneals if needed. The LAS group’s strategy may be a safer strategy in that a less plantar-flexed position of the ankle is more close-packed and stable. Further, it appears the long-latency response of the peroneals may be enhanced in these individuals, which indicates motor learning at the supraspinal level to promote dynamic restraint. Clinical Relevance: Individuals with AI can increase peroneal activation when necessary to dynamically stabilize the ankle, indicating the potential for training/rehabilitation. Further, the LAS group may deploy a different control strategy after injury to protect the ankle from subsequent sprains, which deserves investigation during activities of daily living. A greater understanding of these strategies will lead to the development of more appropriate treatment paradigms after injury to minimize the incidence of instability.
Molecular evolution under increasing transposable element burden in Drosophila: A speed limit on the evolutionary arms race
Authors: Castillo Dean M , Mell Joshua Chang , Box Kimberly S , Blumenstiel Justin P 
Published: September 2011

Abstract

Background
Genome architecture is profoundly influenced by transposable elements (TEs), and natural selection against their harmful effects is a critical factor limiting their spread. Genome defense by the piRNA silencing pathway also plays a crucial role in limiting TE proliferation. How these two forces jointly determine TE abundance is not well understood. To shed light on the nature of factors that predict TE success, we test three distinct hypotheses in the Drosophila genus. First, we determine whether TE abundance and relaxed genome-wide purifying selection on protein sequences are positively correlated. This serves to test the hypothesis that variation in TE abundance in the Drosophila genus can be explained by the strength of natural selection, relative to drift, acting in parallel against mildly deleterious non-synonymous mutations. Second, we test whether increasing TE abundance is correlated with an increased rate of amino-acid evolution in genes encoding the piRNA machinery, as might be predicted by an evolutionary arms race model. Third, we test whether increasing TE abundance is correlated with greater codon bias in genes of the piRNA machinery. This is predicted if increasing TE abundance selects for increased efficiency in the machinery of genome defense.

Results
Surprisingly, we find neither of the first two hypotheses to be true. Specifically, we found that genome-wide levels of purifying selection, measured by the ratio of non-synonymous to synonymous substitution rates (ω), were greater in species with greater TE abundance. In addition, species with greater TE abundance have greater levels of purifying selection in the piRNA machinery. In contrast, it appears that increasing TE abundance has primarily driven adaptation in the piRNA machinery by increasing codon bias.

Conclusions
These results indicate that within the Drosophila genus, a historically reduced strength of selection relative to drift is unlikely to explain patterns of increased TE success across species. Other factors, such as ecological exposure, are likely to contribute to variation in TE abundances within species. Furthermore, constraints on the piRNA machinery may temper the evolutionary arms race that would drive increasing rates of evolution at the amino acid level. In the face of these constraints, selection may act primarily by improving the translational efficiency of the machinery of genome defense through efficient codon usage.