bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Binding of β-Lactam Antibiotics in Critically Ill Patients: Can We Successfully Predict Unbound Concentrations?
Authors: Wong Gloria , Briscoe Scott , Adnan Syamhanin , McWhinney Brett , Ungerer Jacobus , Lipman Jeffrey , Roberts Jason A. 
Published: October 2013

ABSTRACT

The use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there are limited data describing the potential impact of altered protein binding on achievement of target concentrations. The aim of this study was to compare the measured unbound concentration to the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood samples obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 220 plasma samples at the midpoint of the dosing interval and trough, respectively, for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentrations were marked for all antibiotics, with significant differences being present between measured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval (
P
< 0.05). The predictive performance for calculating unbound concentrations using published protein binding values was poor, with bias for overprediction of unbound concentrations for ceftriaxone (83.3%), flucloxacillin (56.8%), and benzylpenicillin (25%) and underprediction for meropenem (12.1%). Linear correlations between the measured total and unbound concentrations were observed for all beta-lactams (
R
2
= 0.81 to 1.00;
P
< 0.05) except ceftriaxone and flucloxacillin. The percent protein binding of flucloxacillin and the plasma albumin concentration were also found to be linearly correlated (
R
2
= 0.776;
P
< 0.01). In conclusion, significant differences between measured and predicted unbound drug concentrations were found only for the highly protein-bound beta-lactams ceftriaxone and flucloxacillin. However, direct measurement of unbound drug in research and clinical practice is suggested for selected beta-lactams.
One-Month Transplacental Pharmacokinetics of Raltegravir in a Premature Newborn after Short-Course Treatment of the HIV-1-Infected Mother
Authors: Clavel-Osorio C. , Cazassus F. , Stegmann S. , Huc-Anaïs P. , Lecam D. , Peytavin G. 
Published: October 2013

ABSTRACT
We describe the pharmacokinetics of raltegravir of a preterm newborn after short-course treatment of the mother tested HIV + the day of delivery. At age 1 month, the circulating concentration of raltegravir in the newborn was 29 ng/ml (the IC95 of RAL against HIV-1 is 15 ng/ml). Raltegravir should therefore be considered a potential transplacental postexposure prophylaxis for HIV-1 and an alternative to the use of boosted lopinavir in this context.
High-Dose Daptomycin Therapy for Left-Sided Infective Endocarditis: a Prospective Study from the International Collaboration on Endocarditis
Authors: Carugati Manuela , Bayer Arnold S. , Miró Josè M. , Park Lawrence P. , Guimarães Armenio C. , Skoutelis Athanasios , Fortes Claudio Q. , Durante-Mangoni Emanuele , Hannan Margaret M. , Nacinovich Francisco , Fernández-Hidalgo Nuria , Grossi Paolo , Tan Ru-San , Holland Thomas , Fowler Vance G. , Corey Ralph G. , Chu Vivian H. 
Published: October 2013

ABSTRACT

The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to
Staphylococcus aureus
, coagulase-negative staphylococci, and
Enterococcus faecalis
, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant
S. aureus
(MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days;
P
< 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.
Vaginolysin Drives Epithelial Ultrastructural Responses to Gardnerella vaginalis
Authors: Randis Tara M. , Zaklama Joanne , LaRocca Timothy J. , Los Ferdinand C. O. , Lewis Emma L. , Desai Purnahamsi , Rampersaud Ryan , Amaral Fábio E. , Ratner Adam J. 
Published: October 2013

ABSTRACT

Gardnerella vaginalis
, the bacterial species most frequently isolated from women with bacterial vaginosis (BV), produces a cholesterol-dependent cytolysin (CDC), vaginolysin (VLY). At sublytic concentrations, CDCs may initiate complex signaling cascades crucial to target cell survival. Using live-cell imaging, we observed the rapid formation of large membrane blebs in human vaginal and cervical epithelial cells (VK2 and HeLa cells) exposed to recombinant VLY toxin and to cell-free supernatants from growing liquid cultures of
G. vaginalis
. Binding of VLY to its human-specific receptor (hCD59) is required for bleb formation, as antibody inhibition of either toxin or hCD59 abrogates this response, and transfection of nonhuman cells (CHO-K1) with hCD59 renders them susceptible to toxin-induced membrane blebbing. Disruption of the pore formation process (by exposure to pore-deficient toxoids or pretreatment of cells with methyl-β-cyclodextrin) or osmotic protection of target cells inhibits VLY-induced membrane blebbing. These results indicate that the formation of functional pores drives the observed ultrastructural rearrangements. Rapid bleb formation may represent a conserved response of epithelial cells to sublytic quantities of pore-forming toxins, and VLY-induced epithelial cell membrane blebbing in the vaginal mucosa may play a role in the pathogenesis of BV.
Coxiella burnetii Interaction with Neutrophils and Macrophages
In Vitro
and in SCID Mice following Aerosol Infection
Authors: Elliott Alexandra , Peng Ying , Zhang Guoquan 
Published: October 2013

ABSTRACT

Coxiella burnetii
is an obligate intracellular bacterium that causes acute and chronic Q fever in humans. Human Q fever is mainly transmitted by aerosol infection. However, there is a fundamental gap in the knowledge regarding the mechanisms of pulmonary immunity against
C. burnetii
infection. This study focused on understanding the interaction between
C. burnetii
and innate immune cells
in vitro
and
in vivo
. Both virulent
C. burnetii
Nine Mile phase I (NMI) and avirulent Nine Mile phase II (NMII) were able to infect neutrophils, while the infection rates were lower than 29%, suggesting that
C. burnetii
can infect neutrophils, but infection is limited. Interestingly,
C. burnetii
inside neutrophils can infect and replicate within macrophages, suggesting that neutrophils cannot kill
C. burnetii
and
C. burnetii
may be using infection of neutrophils as an evasive strategy to infect macrophages. To elucidate the mechanisms of the innate immune response to
C. burnetii
natural infection, SCID mice were exposed to aerosolized
C. burnetii
. Surprisingly, neutrophil influx into the lungs was delayed until day 7 postinfection in both NMI- and NMII-infected mice. This result suggests that neutrophils may play a unique role in the early immune response against aerosolized
C. burnetii
. Studying the interaction between
C. burnetii
and the innate immune system can provide a model system for understanding how the bacteria evade early immune responses to cause infection.
The temporal relationship between drug supply indicators: an audit of international government surveillance systems
Authors: Werb Dan , Kerr Thomas , Nosyk Bohdan , Strathdee Steffanie , Montaner Julio , Wood Evan 
Published: October 2013

ObjectivesIllegal drug use continues to be a major threat to community health and safety. We used international drug surveillance databases to assess the relationship between multiple long-term estimates of illegal drug price and purity.DesignWe systematically searched for longitudinal measures of illegal drug supply indicators to assess the long-term impact of enforcement-based supply reduction interventions.SettingData from identified illegal drug surveillance systems were analysed using an a priori defined protocol in which we sought to present annual estimates beginning in 1990. Data were then subjected to trend analyses.Main outcome measuresData were obtained from government surveillance systems assessing price, purity and/or seizure quantities of illegal drugs; systems with at least 10 years of longitudinal data assessing price, purity/potency or seizures were included.ResultsWe identified seven regional/international metasurveillance systems with longitudinal measures of price or purity/potency that met eligibility criteria. In the USA, the average inflation-adjusted and purity-adjusted prices of heroin, cocaine and cannabis decreased by 81%, 80% and 86%, respectively, between 1990 and 2007, whereas average purity increased by 60%, 11% and 161%, respectively. Similar trends were observed in Europe, where during the same period the average inflation-adjusted price of opiates and cocaine decreased by 74% and 51%, respectively. In Australia, the average inflation-adjusted price of cocaine decreased 14%, while the inflation-adjusted price of heroin and cannabis both decreased 49% between 2000 and 2010. During this time, seizures of these drugs in major production regions and major domestic markets generally increased.ConclusionsWith few exceptions and despite increasing investments in enforcement-based supply reduction efforts aimed at disrupting global drug supply, illegal drug prices have generally decreased while drug purity has generally increased since 1990. These findings suggest that expanding efforts at controlling the global illegal drug market through law enforcement are failing.
Hardware architectural support for control systems and sensor processing
Authors: Vyas Sudhanshu , Gupte Adwait , Gill Christopher D. , Cytron Ron K. , Zambreno Joseph , Jones Phillip H. 
Published: October 2013

The field of modern control theory and the systems used to implement these controls have shown rapid development over the last 50 years. It was often the case that those developing control algorithms could assume the computing medium was solely dedicated to the task of controlling a plant, for example, the control algorithm being implemented in software on a dedicated Digital Signal Processor (DSP), or implemented in hardware using a simple dedicated Programmable Logic Device (PLD). As time progressed, the drive to place more system functionality in a single component (reducing power, cost, and increasing reliability) has made this assumption less often true. Thus, it has been pointed out by some experts in the field of control theory (e.g., Astrom) that those developing control algorithms must take into account the effects of running their algorithms on systems that will be shared with other tasks. One aspect of the work presented in this article is a hardware architecture that allows control developers to maintain this simplifying assumption. We focus specifically on the Proportional-Integral-Derivative (PID) controller. An on-chip coprocessor has been implemented that can scale to support servicing hundreds of plants, while maintaining microsecond-level response times, tight deterministic control loop timing, and allowing the main processor to service noncontrol tasks.
In order to control a plant, the controller needs information about the plant's state. Typically this information is obtained from sensors with which the plant has been instrumented. There are a number of common computations that may be performed on this sensor data before being presented to the controller (e.g., averaging and thresholding). Thus in addition to supporting PID algorithms, we have developed a Sensor Processing Unit (SPU) that off-loads these common sensor processing tasks from the main processor.
We have prototyped our ideas using Field Programmable Gate Array (FPGA) technology. Through our experimental results, we show our PID execution unit gives orders of magnitude improvement in response time when servicing many plants, as compared to a standard general software implementation. We also show that the SPU scales much better than a general software implementation. In addition, these execution units allow the simplifying assumption of dedicated computing medium to hold for control algorithm development.
Cytoplasmic Irradiation Results in Mitochondrial Dysfunction and DRP1-Dependent Mitochondrial Fission
Authors: Zhang Bo , Davidson Mercy M. , Zhou Hongning , Wang Chunxin , Walker Winsome F. , Hei Tom K. 
Published: October 2013

Abstract
Direct DNA damage is often considered the primary cause of cancer in patients exposed to ionizing radiation or environmental carcinogens. Although mitochondria are known to play an important role in radiation-induced cellular response, the mechanisms by which cytoplasmic stimuli modulate mitochondrial dynamics and functions are largely unknown. In the present study, we examined changes in mitochondrial dynamics and functions triggered by α particle damage to the mitochondria in human small airway epithelial cells, using a precision microbeam irradiator with a beam width of 1 μm. Targeted cytoplasmic irradiation using this device resulted in mitochondrial fragmentation and a reduction of cytochrome c oxidase and succinate dehydrogenase activity, when compared with nonirradiated controls, suggesting a reduction in respiratory chain function. In addition, mitochondrial fragmentation or fission was associated with increased expression of the dynamin-like protein DRP1, which promotes mitochondrial fission. DRP1 inhibition by the drug mdivi-1 prevented radiation-induced mitochondrial fission, but respiratory chain function in mitochondria inhibited by radiation persisted for 12 hours. Irradiated cells also showed an increase in mitochondria-derived superoxide that could be quenched by dimethyl sulfoxide. Taken together, our results provide a mechanistic explanation for the extranuclear, nontargeted effects of ionizing radiation. Cancer Res; 73(22); 6700–10. ©2013 AACR.
Senescent Fibroblasts in Melanoma Initiation and Progression: An Integrated Theoretical, Experimental, and Clinical Approach
Authors: Kim Eunjung , Rebecca Vito , Fedorenko Inna V. , Messina Jane L. , Mathew Rahel , Maria-Engler Silvya S. , Basanta David , Smalley Keiran S.M. , Anderson Alexander R.A. 
Published: October 2013

Abstract
We present an integrated study to understand the key role of senescent fibroblasts in driving melanoma progression. Based on the hybrid cellular automata paradigm, we developed an in silico model of normal skin. The model focuses on key cellular and microenvironmental variables that regulate interactions among keratinocytes, melanocytes, and fibroblasts, key components of the skin. The model recapitulates normal skin structure and is robust enough to withstand physical as well as biochemical perturbations. Furthermore, the model predicted the important role of the skin microenvironment in melanoma initiation and progression. Our in vitro experiments showed that dermal fibroblasts, which are an important source of growth factors in the skin, adopt a secretory phenotype that facilitates cancer cell growth and invasion when they become senescent. Our coculture experiments showed that the senescent fibroblasts promoted the growth of nontumorigenic melanoma cells and enhanced the invasion of advanced melanoma cells. Motivated by these experimental results, we incorporated senescent fibroblasts into our model and showed that senescent fibroblasts transform the skin microenvironment and subsequently change the skin architecture by enhancing the growth and invasion of normal melanocytes. The interaction between senescent fibroblasts and the early-stage melanoma cells leads to melanoma initiation and progression. Of microenvironmental factors that senescent fibroblasts produce, proteases are shown to be one of the key contributing factors that promoted melanoma development from our simulations. Although not a direct validation, we also observed increased proteolytic activity in stromal fields adjacent to melanoma lesions in human histology. This leads us to the conclusion that senescent fibroblasts may create a prooncogenic skin microenvironment that cooperates with mutant melanocytes to drive melanoma initiation and progression and should therefore be considered as a potential future therapeutic target. Interestingly, our simulations to test the effects of a stroma-targeting therapy that negates the influence of proteolytic activity showed that the treatment could be effective in delaying melanoma initiation and progression. Cancer Res; 73(23); 6874–85. ©2013 AACR.
JAK1/2 and Pan-Deacetylase Inhibitor Combination Therapy Yields Improved Efficacy in Preclinical Mouse Models of JAK2V617F-Driven Disease
Authors: Evrot Emeline , Ebel Nicolas , Romanet Vincent , Roelli Claudia , Andraos Rita , Qian Zhiyan , Dölemeyer Arno , Dammassa Ernesta , Sterker Dario , Cozens Robert , Hofmann Francesco , Murakami Masato , Baffert Fabienne , Radimerski Thomas 
Published: October 2013

Abstract
Purpose: The myeloproliferative neoplasm myelofibrosis is characterized by frequent deregulation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, and JAK inhibitors were shown to reduce splenomegaly and ameliorate disease-related symptoms. However, the mutant clone and bone marrow fibrosis persist in the majority of patients. Using preclinical models, we explored whether JAK and pan-deacetylase inhibitor combination yielded additional benefits.
Experimental Design: The combination of the JAK1/2 inhibitor ruxolitinib and panobinostat was investigated using two different mouse models of JAK2V617F-driven disease. A Ba/F3 JAK2V617F cell–driven leukemic disease model was used to identify tolerated and efficacious doses. The drugs were then evaluated alone and in combination in a mouse model of myeloproliferative neoplasm–like disease based on transplantation of bone marrow transduced with a retrovirus expressing JAK2V617F. Exposures were determined in blood and tissues, and phosphorylated STAT5 and acetylated histone H3 pharmacodynamic readouts were assessed in spleen and bone marrow. Histologic analysis was conducted on spleen and bone marrow, including staining of reticulin fibers in the latter organ.
Results: The combination of ruxolitinib and panobinostat was found to have a more profound effect on splenomegaly, as well as on bone marrow and spleen histology, compared with either agent alone, and the analysis of pharmacodynamic readouts showed that ruxolitinib and panobinostat have nonoverlapping and complementary effects.
Conclusion: Combining JAK1/2 and pan-deacetylase inhibitors was fairly well tolerated and resulted in improved efficacy in mouse models of JAK2V617F-driven disease compared with the single agents. Thus, the combination of ruxolitinib and panobinostat may represent a promising novel therapeutic modality for myeloproliferative neoplasms. Clin Cancer Res; 19(22); 6230–41. ©2013 AACR.
Chemopreventive Efficacy of Raloxifene, Bexarotene, and Their Combination on the Progression of Chemically Induced Colon Adenomas to Adenocarcinomas in Rats
Authors: Janakiram Naveena B. , Mohammed Altaf , Zhang Yuting , Brewer Misty , Bryant Taylor , Lightfoot Stan , Steele Vernon E. , Rao Chinthalapally V. 
Published: October 2013

Abstract
Estrogen receptor (ER)-β signaling is associated positively in colon tumor progression, whereas downregulation or loss of function of retinoid X receptor (RXR)-α occurs in colon tumors. The chemopreventive efficacies of the estrogen antagonist raloxifene and the selective RXR agonist bexarotene were tested individually and in combination, during promotion and progression stages of colon tumorigenesis. Colon tumors were induced in male F344 rats with azoxymethane and at early adenoma stage, groups of rats (36 or 45 per group) were fed diets containing raloxifene (1.5 or 3 ppm), bexarotene (50 or 100 ppm), or their low-dose combinations for 40 weeks. Raloxifene or bexarotene alone significantly suppressed colon adenocarcinoma formation in terms of multiplicities (mean ± SE): control, 3.59 ± 0.25; 1.5 ppm raloxifene, 2.51 ± 0.29 (P &lt; 0.004); 3 ppm raloxifene, 2.14 ± 0.28 (P &lt; 0.0001); 50 ppm bexarotene, 2.25 ± 0.32 (P &lt; 0.001); 100 ppm bexarotene, 2.1 ± 0.27 (P &lt; 0.0001); and 1.5 ppm raloxifene + 50 ppm bexarotene, 1.57 ± 0.21 (P &lt; 0.0001). The low-dose combination caused significant (56%) inhibition of adenocarcinomas as compared with control diet fed rats. Tumors exposed to raloxifene, bexarotene and/or the combination showed significant suppression of proliferating cell nuclear antigen, cyclin D1, and β-catenin with an increased apoptotic cells (3-fold) and p21 expression (3.8-fold) as compared tumors of rats fed control diet. The combination of low doses of raloxifene and bexarotene significantly suppressed the progression of colonic adenomas to adenocarcinomas and may be useful for colon cancer prevention and/or treatment in high-risk individuals. Cancer Prev Res; 6(12); 1251–61. ©2013 AACR.