bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment
Authors: Ikawa Kazuro , Nakashima Akira , Morikawa Norifumi , Ikeda Kayo , Murakami Yoshiaki , Ohge Hiroki , Derendorf Hartmut , Sueda Taijiro 
Published: September 2011

ABSTRACT

The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (
n
= 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (≥90%) against
Escherichia coli
,
Klebsiella pneumoniae
, and
Enterobacter cloacae
isolates. However, against
Pseudomonas aeruginosa
isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was ≥90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.
Quantifying the Impact of Nevirapine-Based Prophylaxis Strategies To Prevent Mother-to-Child Transmission of HIV-1: a Combined Pharmacokinetic, Pharmacodynamic, and Viral Dynamic Analysis To Predict Clinical Outcomes
Authors: Frank M. , von Kleist M. , Kunz A. , Harms G. , Schütte C. , Kloft C. 
Published: September 2011

ABSTRACTSingle-dose nevirapine (sd-NVP) and extended NVP prophylaxis are widely used in resource-constrained settings to prevent vertical HIV-1 transmission. We assessed the pharmacokinetics of sd-NVP in 62 HIV-1-positive pregnant Ugandan woman and their newborns who were receiving sd-NVP prophylaxis to prevent mother-to-child HIV-1 transmission. Based on these data, we developed a mathematical model system to quantify the impact of different sd-NVP regimens at delivery and of extended infant NVP prophylaxis (6, 14, 21, 26, 52, 78, and 102 weeks) on the 2-year risk of HIV-1 transmission and development of drug resistance in mothers and their breast-fed infants. Pharmacokinetic parameter estimates and model-predicted HIV-1 transmission rates were very consistent with other studies. Predicted 2-year HIV-1 transmission risks were 35.8% without prophylaxis, 31.6% for newborn sd-NVP, 19.1% for maternal sd-NVP, and 19.7% for maternal/newborn sd-NVP. Maternal sd-NVP reduced newborn infection predominately by transplacental exchange, providing protective NVP concentrations to the newborn at delivery, rather than by maternal viral load reduction. Drug resistance was frequently selected in HIV-1-positive mothers after maternal sd-NVP. Extended newborn NVP prophylaxis further decreased HIV-1 transmission risks, but an overall decline in cost-effectiveness for increasing durations of newborn prophylaxis was indicated. The total number of infections with resistant virus in newborns was not increased by extended newborn NVP prophylaxis. The developed mathematical modeling framework successfully predicted the risk of HIV-1 transmission and resistance development and can be adapted to other drugs/drug combinations toa prioriassess their potential in reducing vertical HIV-1 transmission and resistance spread.
Interleukin-10 Alters Effector Functions of Multiple Genes Induced by Borrelia burgdorferi in Macrophages To Regulate Lyme Disease Inflammation
Authors: Gautam Aarti , Dixit Saurabh , Philipp Mario T. , Singh Shree R. , Morici Lisa A. , Kaushal Deepak , Dennis Vida A. 
Published: September 2011

ABSTRACTInterleukin-10 (IL-10) modulates inflammatory responses elicitedin vitroandin vivobyBorrelia burgdorferi, the Lyme disease spirochete. How IL-10 modulates these inflammatory responses still remains elusive. We hypothesize that IL-10 inhibits effector functions of multiple genes induced byB. burgdorferiin macrophages to control concomitantly elicited inflammation. Because macrophages are essential in the initiation of inflammation, we used mouse J774 macrophages and liveB. burgdorferispirochetes as the model target cell and stimulant, respectively. First, we employed transcriptome profiling to identify genes that were induced by stimulation of cells with live spirochetes and that were perturbed by addition of IL-10 to spirochete cultures. Spirochetes significantly induced upregulation of 347 genes at both the 4-h and 24-h time points. IL-10 inhibited the expression levels, respectively, of 53 and 65 of the 4-h and 24-h genes, and potentiated, respectively, at 4 h and 24 h, 65 and 50 genes. Prominent among the novel identified IL-10-inhibited genes also validated by quantitative real-time PCR (qRT-PCR) were Toll-like receptor 1 (TLR1), TLR2, IRAK3, TRAF1, IRG1, PTGS2, MMP9, IFI44, IFIT1, and CD40. Proteome analysis using a multiplex enzyme-linked immunosorbent assay (ELISA) revealed the IL-10 modulation/and or potentiation of RANTES/CCL5, macrophage inflammatory protein 2 (MIP-2)/CXCL2, IP-10/CXCL10, MIP-1α/CCL3, granulocyte colony-stimulating factor (G-CSF)/CSF3, CXCL1, CXCL5, CCL2, CCL4, IL-6, tumor necrosis factor alpha (TNF-α), IL-1α, IL-1β, gamma interferon (IFN-γ), and IL-9. Similar results were obtained using sonicated spirochetes or lipoprotein as stimulants. Our data show that IL-10 alters effectors induced byB. burgdorferiin macrophages to control concomitantly elicited inflammatory responses. Moreover, for the first time, this study provides global insight into potential mechanisms used by IL-10 to control Lyme disease inflammation.
Mycobacterium tuberculosis Hip1 Dampens Macrophage Proinflammatory Responses by Limiting Toll-Like Receptor 2 Activation
Authors: Madan-Lala Ranjna , Peixoto Katia Vitorello , Re Fabio , Rengarajan Jyothi 
Published: September 2011

ABSTRACTMycobacterium tuberculosisis a highly successful human pathogen that evades host innate immunity by interfering with macrophage functions. In addition to avoiding macrophage microbicidal activities,M. tuberculosistriggers secretion of proinflammatory cytokines and chemokines in macrophages. The levels of proinflammatory cytokines induced by clinicalM. tuberculosisisolates are thought to play an important role in determining tuberculosis disease progression and severity, but the mechanisms by whichM. tuberculosismodulates the magnitude of inflammatory responses remain unclear. Here we show thatM. tuberculosisrestricts robust macrophage activation and dampens proinflammatory responses through the cell envelope-associated serine hydrolase Hip1 (hydrolaseimportant forpathogenesis1). By transcriptionally profiling macrophages infected with either wild-type orhip1mutant bacteria, we found that thehip1mutant induced earlier and significantly higher levels of several proinflammatory cytokines and chemokines. We show that increased activation of Toll-like receptor 2 (TLR2)- and MyD88-dependent signaling pathways mediates the enhanced cytokine secretion induced by thehip1mutant. Thus, Hip1 restricts the onset and magnitude of proinflammatory cytokines by limiting TLR2-dependent activation. We also show that Hip1 dampens TLR2-independent activation of the inflammasome and limits secretion of interleukin-18 (IL-18). Dampening of TLR2 signaling does not require viableM. tuberculosisor phagocytosis but does require Hip1 catalytic activity. We propose thatM. tuberculosisrestricts proinflammatory responses by masking cell surface interactions between TLR2 agonists onM. tuberculosisand TLR2 on macrophages. This strategy may allowM. tuberculosisto evade early detection by host immunity, delay the onset of adaptive immune responses, and accelerate disease progression.
Exercise during pregnancy improves maternal glucose screen at 24–28 weeks: a randomised controlled trial
Authors: Barakat Ruben , Cordero Yaiza , Coteron Javier , Luaces Maria , Montejo Rocio 
Published: September 2011

ObjectiveThe influence of an exercise programme performed by healthy pregnant women on maternal glucose tolerance was studied.Study designA physical activity (PA, land/aquatic activities) programme during the entire pregnancy (three sessions per week) was conducted by a qualified instructor. 83 healthy pregnant women were randomly assigned to either an exercise group (EG, n=40) or a control (CG, n=43) group. 50 g maternal glucose screen (MGS), maternal weight gain and several pregnancy outcomes were recorded.ResultsSignificant differences were found between study groups on the 50 g MGS. Values corresponding to the EG (103.8±20.4 mg/dl) were better than those of the CG (126.9±29.5 mg/dl), p=0.000. In addition, no differences in maternal weight gain and no cases of gestational diabetes in EG versus 3 in CG (7%) (p>0.05) were found.ConclusionA moderate PA programme performed during pregnancy improves levels of maternal glucose tolerance.
Three-coloring triangle-free planar graphs in linear time
Authors: Dvořák Zdeněk , Kawarabayashi Ken-Ichi , Thomas Robin 
Published: September 2011

Grötzsch's theorem states that every triangle-free planar graph is 3-colorable, and several relatively simple proofs of this fact were provided by Thomassen and other authors. It is easy to convert these proofs into quadratic-time algorithms to find a 3-coloring, but it is not clear how to find such a coloring in linear time (Kowalik used a nontrivial data structure to construct anO(nlogn) algorithm).We design a linear-time algorithm to find a 3-coloring of a given triangle-free planar graph. The algorithm avoids using any complex data structures, which makes it easy to implement. As a by-product, we give a yet simpler proof of Grötzsch's theorem.
An adaptive and predictive approach for autonomic multirate multicast networks
Authors: Xiong Naixue , Vasilakos Athanasios V. , Yang Laurence T. , Hossain Ekram 
Published: September 2011

Autonomic communications aim at easing the burden of managing complex and dynamic networks, and designing adaptive, self-turning and self-stabilizing networks to provide much needed flexibility and functional scalability. With the ever-increasing number of multicast applications made recently, considerable efforts have been focused on the design of adaptive flow control schemes for autonomic multicast services. The main difficulties in designing an adaptive flow controller for autonomic multicast service are caused by heterogeneous multicast receivers, especially those with large propagation delays, since the feedback arriving at the source is somewhat outdated and can be harmful to the control operations.
To tackle the preceding problem, this article describes a novel, adaptive, and autonomic multicast scheme, the so-called Proportional, Integrative, Derivative plus Neural Network (PIDNN) predictive technique, which consists of two components: the Proportional Integrative plus Derivative (PID) controller and the Back Propagation BP Neural Network (BPNN). In this integrated scheme, the PID controllers are located at the next upstream main branch nodes of the multicast receivers, and have explicit rate algorithms to regulate the receiving rates of the receivers; while the BPNN is located at the multicast source, and predicts the available bandwidth of those longer delay receivers to compute the expected rates of the longer delay receivers. The ultimate sending rate of the multicast source is the maximum of the aforesaid receiving rates that can be accommodated by its participating branches. This network-assisted property is different from the existing control schemes, in that the PIDNN controller can release the irresponsiveness of a multicast flow caused by those long propagation delays from the receivers. By using BPNN, this active scheme makes the control more responsive to the receivers with longer propagation delay. Thus the rate adaptation can be performed in a timely manner, for the sender to respond to network congestion quickly. We analyze the theoretical aspects of the proposed algorithm, show how the control mechanism can be used to design a controller to support multirate multicast transmission based on feedback of explicit rates, and verify this matching using simulations. Simulation results demonstrate that the proposed PIDNN controller avoids overflow of multicast traffic, and performs better than the existing scheme PNN [Tan et al. 2005] and the multicast schemes based on control theory. Moreover, it also performs well in the sense that it achieves high link utilization, quick response, good scalability, high unitary throughput, intra-session fairness and inter-session fairness.
Metabolic Signatures Imaged in Cancer-Induced Cachexia
Authors: Penet Marie-France , Gadiya Mayur M. , Krishnamachary Balaji , Nimmagadda Sridhar , Pomper Martin G. , Artemov Dmitri , Bhujwalla Zaver M. 
Published: September 2011

Abstract
Cancer-induced cachexia is a complex and poorly understood life-threatening syndrome that is characterized by progressive weight loss due to metabolic alterations, depletion of lipid stores, and severe loss of skeletal muscle protein. Gaining the ability to noninvasively image the presence or onset of cachexia is important to better treat this condition, to improve the design and optimization of therapeutic strategies, and to detect the responses to such treatments. In this study, we employed noninvasive magnetic resonance spectroscopic imaging (MRSI) and [18F]fluoro-2-deoxy-d-glucose (18FDG) positron emission tomography (PET) to identify metabolic signatures typical of cachectic tumors, using this information to analyze the types and extents of metabolic changes induced by the onset of cachexia in normal tissues. Cachexia was confirmed by weight loss as well as analyses of muscle tissue and serum. In vivo, cachexia-inducing murine adenocarcinoma (MAC)16 tumors were characterized by higher total choline (tCho) and higher 18FDG uptake than histologically similar noncachectic MAC13 tumors. A profound depletion of the lipid signal was observed in normal tissue of MAC16 tumor–bearing mice but not within the tumor tissue itself. High-resolution 1H magnetic resonance spectroscopy (MRS) confirmed the high tCho level observed in cachectic tumors that occurred because of an increase of free choline and phosphocholine. Higher succinate and lower creatine levels were also detected in cachectic tumors. Taken together, these findings enhance our understanding of the effect of cancer on host organs and tissues as well as promote the development of noninvasive biomarkers for the presence of cachexia and identification of new therapeutic targets. Cancer Res; 71(22); 6948–56. ©2011 AACR.
AGR2 Is a Novel Surface Antigen That Promotes the Dissemination of Pancreatic Cancer Cells through Regulation of Cathepsins B and D
Authors: Dumartin Laurent , Whiteman Hannah J. , Weeks Mark E. , Hariharan Deepak , Dmitrovic Branko , Iacobuzio-Donahue Christine A. , Brentnall Teresa A. , Bronner Mary P. , Feakins Roger M. , Timms John F. , Brennan Caroline , Lemoine Nicholas R. , Crnogorac-Jurcevic Tatjana 
Published: September 2011

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers largely due to disseminated disease at the time of presentation. Here, we investigated the role and mechanism of action of the metastasis-associated protein anterior gradient 2 (AGR2) in the pathogenesis of pancreatic cancer. AGR2 was induced in all sporadic and familial pancreatic intraepithelial precursor lesions (PanIN), PDACs, circulating tumor cells, and metastases studied. Confocal microscopy and flow cytometric analyses indicated that AGR2 localized to the endoplasmic reticulum (ER) and the external surface of tumor cells. Furthermore, induction of AGR2 in tumor cells regulated the expression of several ER chaperones (PDI, CALU, RCN1), proteins of the ubiquitin-proteasome degradation pathway (HIP2, PSMB2, PSMA3, PSMC3, and PSMB4), and lysosomal proteases [cathepsin B (CTSB) and cathepsin D (CTSD)], in addition to promoting the secretion of the precursor form pro-CTSD. Importantly, the invasiveness of pancreatic cancer cells was proportional to the level of AGR2 expression. Functional downstream targets of the proinvasive activity of AGR2 included CTSB and CTSD in vitro, and AGR2, CTSB, and CTSD were essential for the dissemination of pancreatic cancer cells in vivo. Taken together, the results suggest that AGR2 promotes dissemination of pancreatic cancer and that its cell surface targeting may permit new strategies for early detection as well as therapeutic management. Cancer Res; 71(22); 7091–102. ©2011 AACR.
A prospective cohort study of light transmission platelet aggregometry for bleeding disorders: Is testing native platelet-rich plasma non-inferior to testing platelet count adjusted samples?
Authors: Castilloux Jean , Moffat Karen , Liu Yang , Seecharan Jodi , Pai Menaka , Hayward Catherine 
Published: September 2011

SummaryLight transmission platelet aggregometry (LTA) is important to diagnose bleeding disorders. Experts recommend testing LTA with native (N) rather than platelet count adjusted (A) platelet-rich plasma (PRP), although it is unclear if this provides non-inferior, or superior, detection of bleeding disorders. Our goal was to determine if LTA with NPRP is noninferior to LTA with APRP for bleeding disorder assessments. A prospective cohort of patients, referred for bleeding disorder testing, and healthy controls, were evaluated by LTA using common agonists, NPRP and APRP (adjusted to 250 x 109 platelets/l). Recruitment continued until 40 controls and 40 patients with definite bleeding disorders were tested. Maximal aggregation (MA) data were assessed for the detection of abnormalities from bleeding disorders (all causes combined to limit bias), using sample-type specific reference intervals. Areas under receiver-operator curves (AUROC) were evaluated using pre-defined criteria (area differences: <0.15 for non-inferiority, >0 for superiority). Forty-four controls and 209 patients were evaluated. Chart reviews for 169 patients indicated 67 had bleeding disorders, 28 from inherited platelet secretion defects. Mean MA differences between NPRP and APRP were small for most agonists (ranges, controls: −3.3 to 5.8; patients: −3.0 to 13.7). With both samples, reduced MA with two or more agonists was associated with a bleeding disorder. AUROC differences between NPRP and APRP were small and indicated that NPRP were noninferior to APRP for detecting bleeding disorders by LTA, whereas APRP met superiority criteria. Our study validates using either NPRP or APRP for LTA assessments of bleeding disorders.
Congenital Heart Defects and Developmental and Other Psychiatric Disorders
Authors: Olsen Morten , Sørensen Henrik Toft , Hjortdal Vibeke E. , Christensen Thomas D. , Pedersen Lars 
Published: September 2011

Background—
We examined the risk of psychiatric in-patient admissions and out-patient visits among Danish patients with congenital heart defects (CHD).

Methods and Results—
Using the Danish National Registry of Patients, we identified CHD patients born January 1, 1977, to January 1, 2002. For each patient, we randomly selected 10 population-comparison cohort members from the Danish Civil Registration System, matched by sex and birth year. We computed cumulative risk and hazard ratios (HRs) of time to first psychiatric in-patient admission or out-patient visit identified in the Danish Psychiatric Central Registry and adjusted for parents' educational level and parents' psychiatric morbidity. We identified 6927 CHD patients. At 15 years of age, the cumulative risk of psychiatric admissions or out-patient visits was 5.9% (95% confidence interval [CI], 5.2%–6.6%) among CHD patients. The HRs for CHD patients and comparison cohort members aged 0 to 14 years were 1.8 (95% CI: 1.5–2.1) for males and 2.5 (95% CI: 2.0–3.1) for females. For patients aged 15 to 30 years, the HRs were 1.6 (95% CI: 1.2–2.0) for males and 1.0 (95% CI: 0.8–1.3) for females. Congenital heart defect patients, both with and without invasive therapeutic interventions or extracardiac defects or syndromes, had a higher risk of psychiatric in-patient admissions or out-patient visits than comparison cohort members. After restriction of the comparison cohort to patients with diabetes mellitus or asthma (n=2554), the HR was 1.41 (95% CI: 1.07–1.85) for patients aged 0 to 14 years and 0.70 (95% CI: 0.52–0.94) for patients aged 15 to 30 years.

Conclusion—
Congenital heart disease patients with or without invasive therapeutic interventions are at increased risk of developmental and other psychiatric disorders, which seem to develop earlier than in patients with diabetes mellitus or asthma.
The Impact of Land Surface and Atmospheric Initialization on Seasonal Forecasts with CCSM
Authors: Paolino Daniel A. , Kinter James L. , Kirtman Ben P. , Min Dughong , Straus David M. 
Published: September 2011

Abstract
Series of forecast experiments for two seasons investigate the impact of specifying realistic initial states of the land in conjunction with the observed states of the ocean and atmosphere while using the National Center for Atmospheric Research (NCAR) Community Climate System Model, version 3 (CCSM3.0). Since direct soil moisture observations adequate for initialization of the land surface do not exist, this study considers proxy data. The authors are able to successfully initialize all components of the CCSM3.0 and produce a good representation of the mean land surface climate in the first season’s forecast. In comparison with a previous set of forecast experiments that had initialized only the observed ocean state, there is firm evidence that this study produces a better representation of the interannual variability of the soil surface. The representation of soil moisture in the fully initialized seasonal forecasts as measured against the reanalysis is improved, due in part to the ability of the CCSM3.0 to persist large-scale anomalies present in the initial soil state. The improvement in the representation of the land surface, in conjunction with the atmospheric initialization, contributes to a skillful seasonal forecast of surface temperature. There is little evidence of an improved forecast of precipitation over land. Results from this study support the use of the CCSM, originally designed for use as a climate model, as a fully initialized seasonal forecast model. The authors suggest that initialization of the land surface state is crucial for skillful seasonal forecasts made with fully coupled models.