bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitric Oxide Synthase Inhibition Abolishes Exercise-Mediated Protection against Isoproterenol-Induced Cardiac Hypertrophy in Female Mice
Authors: Ren Jiling , Yang Lei , Tian Wencong , Zhu Mengmeng , Liu Jie , Lu Ping , Li Jing , Yang Liang , Qi Zhi
Published: February 2015

Objective: Exercise training (ET) provides a cardioprotective effect against pathological cardiac hypertrophy. Nitric oxide (NO) plays an important role in modulating cardiac hypertrophy. However, few studies explore the relationship between NO signaling and the inhibitory effect of ET on pathological cardiac remodeling. Methods: In this study, we evaluated ET effects on isoproterenol (ISO)-induced cardiac hypertrophy in female mice. Moreover, L-NAME (Nω-nitro-L-arginine methyl ester), a nonselective NO synthase (NOS) inhibitor, was used to assess the involvement of NO signaling in cardiac hypertrophy. Morphological and echocardiographic variables were assessed. Cardiac hypertrophy-related gene expression was detected by real-time PCR and the protein levels of NOS signaling molecules were determined by Western blot. Results:L-NAME treatment prevented the beneficial effects of ET against the increase in heart weight (HW)/body weight (BW), HW/tibia length and lung weight/BW and echocardiographic variables following ISO injection. Also, L-NAME co-administration reversed ET-induced inhibition of myocardial fibrosis and fetal gene reactivation in ISO-treated mice. Furthermore, L-NAME treatment prevented ET-mediated up-regulation of phosphorylated endothelial NOS and plasma NO in ISO-treated mice. Conclusions: Our findings demonstrate that L-NAME treatment could abolish ET-induced cardioprotection against pathological cardiac hypertrophy and that NOS modulation may be involved in the antihypertrophic effects induced by ET.
The Anti-Inflammatory Effects of the Small Molecule Pifithrin-µ on BV2 Microglia
Authors: Fleiss Bobbi , Chhor Vibol , Rajudin Nazurah , Lebon Sophie , Hagberg Henrik , Gressens Pierre , Thornton Claire
Published: February 2015

Neonatal encephalopathy (NE) is a leading cause of childhood death and disability in term infants. Treatment options for perinatal brain injury are limited and developing therapies that target multiple pathways within the pathophysiology of NE are of great interest. Pifithrin-µ (PFT-µ) is a drug with striking neuroprotective abilities in a preclinical model of hypoxia-ischemia (HI)-induced NE wherein cell death is a substantial cause of injury. Work from neurons and tumor cells reports that PFT-µ is able to inhibit p53 binding to the mitochondria, heat shock protein (HSP)-70 substrate binding and activation of the NF-kB pathway. The purpose of this study is to understand whether the neuroprotective effects of PFT-µ also include direct effects on microglia. We utilized the microglial cell line, BV2, and we studied the dose-dependent effect of PFT-µ on M1-like and M2-like phenotype using qRT-PCR and Western blotting, including the requirement for the presence of p53 or HSP-70 in these effects. We also assessed phagocytosis and the effects of PFT-µ on genes within metabolic pathways related to phenotype. We noted that PFT-µ robustly reduced the M1-like (lipopolysaccharide, LPS-induced) BV2 response, spared the LPS-induced phagocytic ability of BV2 and had no effect on the genes related to metabolism and that effects on phenotype were partially dependent on the presence of HSP-70 but not p53. This study demonstrates that the neuroprotective effects of PFT-µ in HI-induced NE may include an anti-inflammatory effect on microglia and adds to the evidence that this drug might be of clinical interest for the treatment of NE.
Increased Posterior Hippocampal Volumes in Children with Lower Increase in Body Mass Index: A 3-Year Longitudinal MRI Study
Authors: Hashimoto Teruo , Takeuchi Hikaru , Taki Yasuyuki , Yokota Susumu , Hashizume Hiroshi , Asano Kohei , Asano Michiko , Sassa Yuko , Nouchi Rui , Kawashima Ryuta
Published: February 2015

People are generally lean during childhood and show more variability in body sizes and shapes later in life. Cortical development generally correlates with body growth. However, in children cortical growth may be impaired with oversized body growth. Inverse correlations between body mass index (BMI) and brain volumes suggest that lean bodies may be associated with increased cortical volume. To clarify the positive effects of a lean body on a child's cortical development, we used MRI to measure brain structures longitudinally in 107 children and adolescents aged 5-16 years. The relationships between changes in BMI and cortical volumes during 3 years of development were investigated, while controlling for age, gender and intracranial volume changes. Voxel-based morphometry analyses revealed that an increase in the volume of the right posterior medial temporal lobe - including the hippocampus and parahippocampal gyrus - was associated with lower BMI increases. No correlations were observed between higher BMI increases and cortical volumes. Our results suggest that keeping a lean body - or not getting fat - during childhood can induce an increase in regional cortical volume rather than impair growth. This is the first longitudinal study showing positive effects of a lean body on cortical development in children.
Perfusion Index in Preterm Infants during the First 3 Days of Life: Reference Values and Relation with Clinical Variables
Authors: Alderliesten Thomas , Lemmers Petra M.A. , Baerts Willem , Groenendaal Floris , van Bel Frank
Published: February 2015

Background: The perfusion index (PI) derived from pulse oximetry readings represents the ratio of pulsatile (arterial blood) and nonpulsatile contributors to infrared light absorption. PI has been shown to correlate with cardiac performance. In theory, PI is readily available on every pulse oximeter; therefore, no additional sensors or infant handling are required. Currently, reference values are lacking in (preterm) neonates and the association with common clinical conditions is unclear. Objectives: To establish reference values for the PI in premature infants and at the same time determine the influence of common clinical conditions. Methods: PI was prospectively monitored on the lower limb for 72 h in 311 neonates born with a gestational age <32 weeks between January 2011 and December 2013. Longitudinal mixed-effects modeling was used. Linear, quadratic, and cubic models were explored. Main effects and interactions were investigated. Results: A squared model (0-24 h) followed by a linear model (24-72 h) provided the best fit of the data. PI was lowest around 12-18 h after birth and showed a steady increase thereafter. PI was positively related with female gender, gestational age, and pulse pressure. Negative associations were found with SIMV/HFOV ventilation, dopamine administration, mean arterial blood pressure, and arterial oxygen saturation. Although more complex, the general association with a patent ductus arteriosus was positive. Conclusion: PI varied according to several clinical conditions. The association with common clinical factors suggests that PI might be used for monitoring neonatal hemodynamics and possibly as an additional guidance for interventions.
TLR2 Involved in Naive CD4+ T Cells Rescues Stress-Induced Immune Suppression by Regulating Th1/Th2 and Th17
Authors: Zhao Jing , Liu Jing , Denney James , Li Chen , Li Fang , Chang Fen , Chen Mingyou , Yin Deling
Published: February 2015

Stress, either physical or psychological, can have a dramatic impact on our immune system. There has been little progress, however, in understanding chronic stress-induced immunosuppression. Naive CD4+ T cells could modulate immune responses via differentiation to T helper (Th) cells. In this study, we showed that stress promotes the release of the Th1 cytokines interferon (IFN)-γ and tumor necrosis factor (TNF)-α, the Th2 cytokines interleukin (IL)-4 and IL-10 and the Th17 cytokine IL-17 of splenic naive CD4+ T cells. This suggests that stress promotes the differentiation of naive CD4+ T cells to Th1, Th2 and Th17 cells. Knockout strategies verified that TLR2 might modulate the differentiation of Th1/Th2 cells by inhibiting p38 mitogen-activated protein kinase (MAPK). Taken together, our data suggest that chronic stress induces immune suppression by targeting TLR2 and p38 MAPK in naive CD4+ T cells.
Early Secreted Antigen ESAT-6 of Mycobacterium Tuberculosis Promotes Apoptosis of Macrophages via Targeting the MicroRNA155-SOCS1 Interaction
Authors: Yang Shaojun , Li Fake , Jia Shuangrong , Zhang Kejun , Jiang Wenbing , Shang Ya , Chang Kai , Deng Shaoli , Chen Ming
Published: February 2015

Background: The early secreted antigenic target 6-kDa protein (ESAT-6) of Mycobacterium tuberculosis (Mtb) not only acts as a key player for virulence but also exhibits a strong immunotherapeutic potential against Mtb. However, little is known about the molecular basis for its potential in immunotherapy. The present study was designed to unravel the role of miRNA-155 in ESAT-6-mediated enhancement of host immunity and apoptosis in macrophages. Methods: Lentivirus-mediated miR-155 sponge and miR-155 and SOCS1 overexpression vectors were developed in macrophages. TLR2- or p65-specific siRNA knockdown was employed to silence TLR2 or p65. Quantitative polymerase chain reaction and western blotting analyses were performed to determine mRNA and protein expression levels, respectively. Macrophage apoptosis was analyzed by flow cytometry. Results: ESAT-6 significantly increased miR-155 expression, which was dependent on TLR2/NF-κB activation in macrophages. Induced expression of miRNA-155 was required for the ESAT-6-mediated protective immune response and macrophage apoptosis. ESAT-6 promoted macrophage apoptosis by targeting the miR-155-SOCS1 pathway. The differential expression levels of TLR2, BIC, and SOCS1 were involved in regulating the immune response in human peripheral blood mononuclear cells of patients with active tuberculosis (TB) and latent TB (LTB). Conclusion: ESAT-6 promotes apoptosis of macrophages via targeting the miRNA155-SOCS1 interaction.
Wnt1 Positively Regulates CD36 Expression via TCF4 and PPAR-γ in Macrophages
Authors: Wang Shuai , Sun Zewei , Zhang Xi , Li Zhenwei , Wu Mingjie , Zhao Wenting , Wang Houhong , Chen Ting , Yan Hui , Zhu Jianhua
Published: February 2015

Background: Scavenger receptors including CD36 control the phagocytosis of oxidized low-density lipoprotein and play an important role in macrophage physiology, but the underlying molecular mechanism by which CD36 is regulated in macrophages or during macrophage differentiation from monocytes remains to be determined. Methods: Here, we investigated the relationship between Wnt1 and CD36 during macrophage differentiation. CD36 was suppressed following knockdown of Wnt1 by siRNA, while it was increased by ectopic overexpression of Wnt1 in macrophages. Using a β-catenin inhibitor, peroxisome proliferator-activated receptor gamma (PPAR-γ) siRNA, and transcription factor 4 (TCF4) siRNA, we demonstrated that Wnt1 regulates the expression of CD36 through TCF4 and PPAR-γ. Co-immunoprecipitation, chromatin immunoprecipitation, and immunofluorescence experiments showed that β-catenin interacted with PPAR-γ and that PPAR-γ and TCF4 colocalized in the nucleus. Furthermore, Pax3 regulated Wnt1 via binding to the first binding site in the Wnt1 promoter. Results: Our study demonstrated that during macrophage differentiation from monocytes, Wnt1 promotes CD36 expression via activation of PPAR-γ and TCF4. Conclusions: Our findings suggest that Wnt1 plays an important role in macrophage physiology via activation of the canonical Wnt pathway.
Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells
Authors: Li Chenguang , Liu Yaohua , Liu Huailei , Zhang Weiguang , Shen Chen , Cho KenKa , Chen Xin , Peng Fei , Bi Yunke , Hou Xu , Yang Zhuowen , Zheng Zhixing , Wang Kaikai , Wang Xiaoxiong , Zhang Jiakang , Zhong Chen , Zou Huichao , Zhang Xinjian , Zhao Shiguang
Published: February 2015

Background/Aims: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a poor prognosis. Combination treatment of autophagy inducer and autophagy inhibitor may be a feasible solution to improve the therapeutic effects. However, the correlation between them is unclear. The purpose of this study was to investigate the effect of autophagy inhibition at different stages on cytotoxicity of autophagy inducers in glioblastoma cells. Methods: Autophagy inhibition at early stage was achieved by 3-methyladenine (3-MA) or Beclin 1 shRNA. Autophagy inhibition at late stage was achieved by chloroquine (CQ) or Rab7 shRNA. Cell viability was assessed by MTT assay. Autophagy was measured using transmission electron microscopy and western blot. Apoptosis was measured using western blot and flow-cytometry. Results: Inhibition of early steps of autophagy by 3-MA or Beclin 1 knockdown decreased the toxic effect of arsenic trioxide (ATO) in GBM cell lines. In contrast, blockade of autophagy flux at late stage by CQ or Rab7 knockdown enhanced the cytotoxicity of ATO, and caused accumulation of degradative autophagic vacuoles and robust apoptosis. Moreover, depletion of Beclin 1 abolished the synergistic effect of ATO and CQ by reducing autophagy and apoptosis. Combination of CQ with other autophagy inducers also induced synergistic apoptotic cell death. Conclusion: These results suggest that inhibition of late process of autophagy, not initial step, increases the cytotoxic effect of autophagy inducers via autophagy and apoptosis, which may contribute to GBM chemotherapy.
The Role of Lipid Rafts in the Early Stage of Enterovirus 71 Infection
Authors: Zhu Yong-Zhe , Wu Da-Ge , Ren Hao , Xu Qing-Qiang , Zheng Kui-Cheng , Chen Wei , Chen Sheng-Lin , Qian Xi-Jing , Tao Qing-Yuan , Wang Yan , Zhao Ping , Qi Zhong-Tian
Published: February 2015

Background/Aims: Although it has been widely accepted that Enterovirus 71 (EV71) enters permissive cells via receptor-mediated endocytosis, the details of entry mechanism for EV71 still need more exploration. This study aimed to investigate the role of lipid rafts in the early stage of EV71 Infection. Methods: The effect of cholesterol depletion or addition of exogenous cholesterol was detected by immunofluorescence assays and quantitative real-time PCR. Effects of cholesterol depletion on the association of EV71 with lipid rafts were determined by flow cytometry and co-immunoprecipitation assays. Localization and internalization of EV71 and its receptor were assayed by confocal microscpoy and sucrose gradient analysis. The impact of cholesterol on the activation of phosphoinositide 3'-kinase/Akt signaling pathway during initial virus infection was analyzed by Western-blotting. Results: Disruption of membrane cholesterol by a pharmacological agent resulted in a significant reduction in the infectivity of EV71. The inhibitory effect could be reversed by the addition of exogenous cholesterol. Cholesterol depletion post-infection did not affect EV71 infection. While virus bound equally to cholesterol-depleted cells, EV71 particles failed to be internalized by cholesterol-depleted cells. EV71 capsid protein co-localized with cholera toxin B, a lipid-raft-dependent internalization marker. Conclusion: Lipid rafts play a critical role in virus endocytosis and in the activation of PI3K/Akt signaling pathway in the early stage of EV71 infection.
“What is California? Nothing but Innumerable Stones”
Authors: Johnston Sky Michael
Published: February 2015

This article examines the records of the last generation of German Jesuit missionaries in California (present-day Baja California). Removed from the colonial Spanish territory in 1768 by edict of the Spanish king, the missionaries formed a narrative of their efforts in California that they then brought back to Europe. In California, the missionaries attributed great spiritual significance to the dry climate of the region. The arid physical environment thwarted the missionaries’ efforts to build the landscape that they believed was vital to the spiritual development of the indigenous Californians. The Jesuits maintained the necessity of their desired landscape even as they came to accept the impossibility of physically creating it in California. Ultimately, the environment occupied a prominent place in the missionaries’ accounts which simultaneously justified their work in California and explained its shortcomings.
Drawing Complaint
Authors: Takemoto Tina
Published: February 2015

Matthew Barney’s 2006 solo exhibition at the San Francisco Museum of Modern Art showcased large-scale sculptures, drawings, and photographs relating to his film Drawing Restraint 9 featuring the artist and his partner Björk on a whaling ship in Japan. This essay examines Barney’s neo-Orientalist project in light of cultural appropriation and discusses the author’s participation in Drawing Complaint: Memoirs of Björk-Geisha, a guerrilla art scheme to interrupt the exhibition opening. The successes and failures of this intervention are considered alongside other artistic practices that deploy disidentification and hyperracial drag to interrogate the consumption of exotic and erotic spectacles only to encounter further exotification or cooptation. This essay also reflects on the instability of disidentificatory interventionist tactics as well as the psychic and personal toll of embodying toxic representations especially for queer artists of color who deliberately perform their own racial and sexual abjection as a mode of critique.
New species, taxonomic renovations, and typifications in Gaultheria series Trichophyllae (Ericaceae)
Authors: Fritsch Peter W , Lu Lu , Wang Hong , Li De-zhu
Published: February 2015

Expeditions to the Gaoligong Mountains and Biluo Snow Mountains in western Yunnan Province, China have uncovered new taxonomic information about the species of Gaultheria series Trichophyllae (Ericaceae) that are known to occur in these ranges. Based on these data, we describe two species as new to science (G. ciliisepala and G. stenophylla) and elevate four varieties (Chiogenes suborbicularis var. albiflorus, G. sinensis vars. crassifolia and major, and G. trichophylla var. obovata) to the species level (as G. albiflora, G. crassifolia, G. major, and G. obovata, respectively). We provide a lectotype and a revised description for G. eciliata because the type was discovered to also include individuals of G. albiflora. Similarly, we provide a lectotype and a revised description for G. sinensis because the type was discovered to also include an individual of G. crassifolia; moreover, the protologue of G. sinensis includes paratypes of three other species. Illustrations and photographic images of living plants in the field are included for all species. Our additions and changes raise the number of species recognized in G. series Trichophyllae from 10 to 16, with more to be expected as the Himalaya-Hengduan Mountains are further surveyed for these plants.
Revision of the orb-weaving spider genus Verrucosa McCook, 1888 (Araneae, Araneidae)
Authors: LISE ARNO A. , KESSTER CYNARA C. , DA SILVA ESTEVAM L. CRUZ
Published: February 2015

The araneid spider genus Verrucosa McCook, 1888 is revised. Five of the seven previously known species, V. arenata (Walckenaer, 1841), V. lampra Soares & Camargo, 1948, V. meridionalis (Keyserling, 1892), V. undecimvariolata (O. Pickard-Cambridge, 1889) and V. zebra (Keyserling, 1892), are redescribed and illustrated. In addition, 37 new species of Verrucosa from the Neotropical region are described and illustrated: V. cachimbo n. sp., V. tarapoa n. sp., V. scapofracta n. sp., V. carara n. sp., V. latigastra n. sp., V. guatopo n. sp., V. cuyuni n. sp., V. benavidesae n. sp., V. rancho n. sp., V. excavata n. sp., V. meta n. sp., V. levii n. sp., V. chanchamayo n. sp., V. manauara n. sp., V. brachiscapa n. sp., V. macarena n. sp., V. pedrera n. sp., V. lata n. sp., V. galianoae n. sp., V. suaita n. sp., V. coroico n. sp., V. florezi n. sp., V. hoferi n. sp., V. caninde n. sp., V. opon n. sp., V. silvae n. sp., V. avilesae n. sp., V. tuberculata n. sp., V. alvarengai n. sp., V. apuela n. sp., V. bartica n. sp., V. cajamarca n. sp., V. canje n. sp., V. cuyabenoensis n. sp., V. sergipana n. sp., V. simla n. sp. and V. rhea n. sp. Mahadiva reticulata O. P.-Cambridge, 1889 is removed from the synonymy of Verrucosa arenata (Walckenaer, 1841) and is recognized as a valid species, Verrucosa reticulata. Araneus cylicophorus Badcock, 1932 is transferred to Verrucosa by Mello-Leitão (1946) removed from the synonymy of Verrucosa meridionalis (Keyserling, 1892) and recognized as a valid species. The male of Verrucosa meridionalis (Keyserling, 1892) is described for the first time. Distributional maps are provided for all species.
Systematic revision of the genus Calligrapha Chevrolat (Coleoptera: Chrysomelidae, Chrysomelinae) in Central America: The group of Calligrapha argus Stål
Authors: GÓMEZ-ZURITA JESÚS
Published: February 2015

Calligrapha Chevrolat is a large American leaf beetle genus of imprecise taxonomic boundaries. Most species occur in Central and South America where they have not been subject to modern systematic revisions. This work is the first attempt to clarify the systematics of the group by focusing on a relatively diverse species group well characterized from a morphological standpoint: the group of C. argus Stål. I provide a pragmatic identification key for major lineages in Calligrapha, highlighting a potentially useful character for supra-specific rank systematics within this genus, namely the shape of the distal end of the flagellum in the penis. This key helps recognizing the C. argus species group as one with species having a single spot enclosed by humeral lunule and a complete arcuate band, laterally confluent with subsutural stripe (except in C. elegantula Jacoby), deep hypomeral furrow and with characteristic ventral carving at apex of flagellum, as major distinguishing features. The species group is subdivided into fourteen species, whereby one previously described taxon, C. famularis Stål, is subordinated as subspecies of C. geographica Stål stat. nov., and two new species from southern Mexico and Guatemala are described: C. anabelae sp. nov. and C. catarinae sp. nov. An identification key for all the species in the group is provided, as well as collection data for the approximately 2,100 specimens determined for this work and distribution maps based on these collection data. The group is centred in the Caribbean Mesoamerican biogeographic domain, with two species reaching the California-Rocky Mountain domain to the north (C. ancoralis Stål and C. diversa Stål), and three species reaching the Caribbean Northwest-South American domain to the south (C. argus Stål, C. diversa Stål and C. simillima Stål).
Idealized Quasi-Biennial Oscillations in an Ensemble of Dry GCM Dynamical Cores
Authors: Yao Weiye , Jablonowski Christiane
Published: February 2015

The paper demonstrates that quasi-biennial oscillation (QBO)-like oscillations can be simulated in an ensemble of dry GCM dynamical cores that are driven by a simple Held–Suarez temperature relaxation and low-level Rayleigh friction. The tropical stratospheric circulations of four dynamical cores, which are options in NCAR’s Community Atmosphere Model, version 5 (CAM5), are intercompared. These are the semi-Lagrangian (SLD) and Eulerian (EUL) spectral transform, finite-volume (FV), and spectral element (SE) dynamical cores. The paper investigates how the model design choices impact the wave generation, propagation, and dissipation mechanisms in the equatorial region. SLD, EUL, and SE develop spontaneous QBO-like oscillations in the upper equatorial stratosphere, whereas FV does not sustain the oscillation. Transformed Eulerian-mean (TEM) analyses reveal that resolved waves are the dominant drivers of the QBOs. However, the Eliassen–Palm flux divergence is strongly counteracted by the TEM momentum budget residual, which represents the forcing by diffusion and thermal damping. Interestingly, a reversed Brewer–Dobson circulation accelerates the downward propagation of the SLD’s QBO, whereas the EUL’s and SE’s QBOs are slowed by a mean ascent. Waves are abundant in the SLD’s, EUL’s, and SE’s tropical atmosphere despite the absence of moist convection as a typical wave trigger. Dynamic instabilities are suggested as a wave-triggering mechanism in the troposphere and wave-dissipation process in the stratosphere. In particular, there are indications that the increased occurrences of strongly negative instability indicators in SLD, EUL, and SE are related to more vigorous wave activities and higher magnitudes of the resolved wave forcing in comparison to FV.
Evaluating Unsupervised Methods to Size and Classify Suspended Particles Using Digital In-Line Holography
Authors: Davies Emlyn J. , Buscombe Daniel , Graham George W. , Nimmo-Smith W. Alex M.
Published: February 2015

Substantial information can be gained from digital in-line holography of marine particles, eliminating depth-of-field and focusing errors associated with standard lens-based imaging methods. However, for the technique to reach its full potential in oceanographic research, fully unsupervised (automated) methods are required for focusing, segmentation, sizing, and classification of particles. These computational challenges are the subject of this paper, in which the authors draw upon data collected using a variety of holographic systems developed at Plymouth University, United Kingdom, from a significant range of particle types, sizes, and shapes. A new method for noise reduction in reconstructed planes is found to be successful in aiding particle segmentation and sizing. The performance of an automated routine for deriving particle characteristics (and subsequent size distributions) is evaluated against equivalent size metrics obtained by a trained operative measuring grain axes on screen. The unsupervised method is found to be reliable, despite some errors resulting from oversegmentation of particles. A simple unsupervised particle classification system is developed and is capable of successfully differentiating sand grains, bubbles, and diatoms from within the surfzone. Avoiding miscounting bubbles and biological particles as sand grains enables more accurate estimates of sand concentrations and is especially important in deployments of particle monitoring instrumentation in aerated water. Perhaps the greatest potential for further development in the computational aspects of particle holography is in the area of unsupervised particle classification. The simple method proposed here provides a foundation upon which further development could lead to reliable identification of more complex particle populations, such as those containing phytoplankton, zooplankton, flocculated cohesive sediments, and oil droplets.
A multicenter study on the effect of continuous hemodiafiltration intensity on antibiotic pharmacokinetics
Authors: Roberts Darren M , Liu Xin , Roberts Jason A , Nair Priya , Cole Louise , Roberts Michael S , Lipman Jeffrey , Bellomo Rinaldo ,   On behalf of the RENAL Replacement Therapy Study Investigators
Published: February 2015

Introduction

Continuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. In a nested cohort within a large randomized controlled trial, we assessed the effect of higher (40 mL/kg per hour) and lower (25 mL/kg per hour) intensity CRRT on antibiotic pharmacokinetics.

Methods

We collected serial blood samples to measure ciprofloxacin, meropenem, piperacillin-tazobactam, and vancomycin levels. We calculated extracorporeal clearance (CL), systemic CL, and volume of distribution (Vd) by non-linear mixed-effects modelling. We assessed the influence of CRRT intensity and other patient factors on antibiotic pharmacokinetics.

Results

We studied 24 patients who provided 179 pairs of samples. Extracorporeal CL increased with higher-intensity CRRT but the increase was significant for vancomycin only (mean 28 versus 22 mL/minute; P = 0.0003). At any given prescribed CRRT effluent rate, extracorporeal CL of individual antibiotics varied widely, and the effluent-to-plasma concentration ratio decreased with increasing effluent flow. Overall, systemic CL varied to a greater extent than Vd, particularly for meropenem, piperacillin, and tazobactam, and large intra-individual differences were also observed. CRRT dose did not influence overall (systemic) CL, Vd, or half-life. The proportion of systemic CL due to CRRT varied widely and was high in some cases.

Conclusions

In patients receiving CRRT, there is great variability in antibiotic pharmacokinetics, which complicates an empiric approach to dosing and suggests the need for therapeutic drug monitoring. More research is required to investigate the apparent relative decrease in clearance at higher CRRT effluent rates.

Trial registration

ClinicalTrials.gov NCT00221013. Registered 14 September 2005.
A simple prognostic index based on admission vital signs data among patients with sepsis in a resource-limited setting
Authors: Asiimwe Stephen B , Abdallah Amir , Ssekitoleko Richard
Published: February 2015

Introduction

In sub-Saharan Africa, vital signs are a feasible option for monitoring critically ill patients. We assessed how admission vital signs data predict in-hospital mortality among patients with sepsis. In particular, we assessed whether vital signs data can be incorporated into a prognostic index with reduced segmentation in the values of included variables.

Methods

Subjects were patients with sepsis hospitalized in Uganda, who participated in two cohort studies. Using restricted cubic splines of admission vital signs data, we predicted probability of in-hospital death in the development cohort and used this information to construct a simple prognostic index. We assessed the performance of the index in a validation cohort and compared its performance to that of the Modified Early Warning Score (MEWS).

Results

We included 317 patients (167 in the development cohort and 150 in the validation cohort). Based on how vital signs predicted mortality, we created a prognostic index giving a score of 1 for: respiratory rates ≥30 cycles/minute; pulse rates ≥100 beats/minute; mean arterial pressures ≥110/<70 mmHg; temperatures ≥38.6/<35.6°C; and presence of altered mental state defined as Glasgow coma score ≤14; 0 for all other values. The proposed index (maximum score = 5) predicted mortality comparably to MEWS. Patients scoring ≥3 on the index were 3.4-fold (95% confidence interval (CI) 1.6 to 7.3, P = 0.001) and 2.3-fold (95% CI 1.1 to 4.7, P = 0.031) as likely to die in hospital as those scoring 0 to 2 in the development and validation cohorts respectively; those scoring ≥5 on MEWS were 2.5-fold (95% CI 1.2 to 5.3, P = 0.017) and 1.8-fold (95% CI 0.74 to 4.2, P = 0.204) as likely to die as those scoring 0 to 4 in the development and validation cohorts respectively.

Conclusion

Among patients with sepsis, a prognostic index incorporating admission vital signs data with reduced segmentation in the values of included variables adequately predicted mortality. Such an index may be more easily implemented when triaging acutely-ill patients. Future studies using a similar approach may develop indexes that can be used to monitor treatment among acutely-ill patients, especially in resource-limited settings.
Efficacy and safety of 6% hydroxyethyl starch 130/0.4 (Voluven) for perioperative volume replacement in children undergoing cardiac surgery: a propensity-matched analysis
Authors: Van der Linden Philippe , Dumoulin Melanie , Van Lerberghe Celine , Torres Cristel Sanchez , Willems Ariane , Faraoni David
Published: February 2015

Introduction

Six percent hydroxyethyl starch (HES) 130/0.4 is considered an alternative to human albumin (HA) and crystalloids for volume replacement in children undergoing cardiac surgery. In this large propensity-matched analysis, we aimed to assess the efficacy and safety of replacing HA with HES for intraoperative volume therapy in children undergoing cardiac surgery with cardiopulmonary bypass (CPB).

Methods

We retrospectively reviewed our database, including children who underwent cardiac surgery between January 2002 and December 2010. Four percent HA was used until 2005; it was replaced by HES thereafter. Demographic data, intra- and postoperative blood loss and blood component transfusions were recorded, together with the incidence of postoperative complications and mortality. We performed a propensity-matched analysis using 13 possible confounding factors to compare children who received either HES or HA intraoperatively. The primary objectives included the effects of both fluids on intraoperative fluid balance (difference between fluids in and fluids out (efficacy)) and blood loss and exposure to allogeneic blood products (safety). Secondary safety outcomes were mortality and the incidence of postoperative renal dysfunction.

Results

Of 1,832 children reviewed, 1,495 were included in the analysis. Intraoperative use of HES was associated with a less positive fluid balance. Perioperative blood loss, volume of red blood cells and fresh frozen plasma administered, as well as the number of children who received transfusions, were also significantly lower in the HES group. No difference was observed regarding the incidence of postoperative renal failure requiring renal replacement therapy or of morbidity and mortality.

Conclusions

These results confirm that the use of HES for volume replacement in children during cardiac surgery with CPB is as safe as HA. In addition, its use might be associated with less fluid accumulation. Further large studies are needed to assess whether the reduction in fluid accumulation could have a significant impact on postoperative morbidity and mortality.
Molecular subtyping for clinically defined breast cancer subgroups
Authors: Zhao Xi , Rødland Einar Andreas , Tibshirani Robert , Plevritis Sylvia
Published: February 2015

Introduction

Breast cancer is commonly classified into intrinsic molecular subtypes. Standard gene centering is routinely done prior to molecular subtyping, but it can produce inaccurate classifications when the distribution of clinicopathological characteristics in the study cohort differs from that of the training cohort used to derive the classifier.

Methods

We propose a subgroup-specific gene-centering method to perform molecular subtyping on a study cohort that has a skewed distribution of clinicopathological characteristics relative to the training cohort. On such a study cohort, we center each gene on a specified percentile, where the percentile is determined from a subgroup of the training cohort with clinicopathological characteristics similar to the study cohort. We demonstrate our method using the PAM50 classifier and its associated University of North Carolina (UNC) training cohort. We considered study cohorts with skewed clinicopathological characteristics, including subgroups composed of a single prototypic subtype of the UNC-PAM50 training cohort (n = 139), an external estrogen receptor (ER)-positive cohort (n = 48) and an external triple-negative cohort (n = 77).

Results

Subgroup-specific gene centering improved prediction performance with the accuracies between 77% and 100%, compared to accuracies between 17% and 33% from standard gene centering, when applied to the prototypic tumor subsets of the PAM50 training cohort. It reduced classification error rates on the ER-positive (11% versus 28%; P = 0.0389), the ER-negative (5% versus 41%; P < 0.0001) and the triple-negative (11% versus 56%; P = 0.1336) subgroups of the PAM50 training cohort. In addition, it produced higher accuracy for subtyping study cohorts composed of varying proportions of ER-positive versus ER-negative cases. Finally, it increased the percentage of assigned luminal subtypes on the external ER-positive cohort and basal-like subtype on the external triple-negative cohort.

Conclusions

Gene centering is often necessary to accurately apply a molecular subtype classifier. Compared with standard gene centering, our proposed subgroup-specific gene centering produced more accurate molecular subtype assignments in a study cohort with skewed clinicopathological characteristics relative to the training cohort.
Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients
Authors: Freitas Alex A , Limbu Kriti , Ghafourian Taravat
Published: February 2015

Background

Volume of distribution is an important pharmacokinetic property that indicates the extent of a drug’s distribution in the body tissues. This paper addresses the problem of how to estimate the apparent volume of distribution at steady state (Vss) of chemical compounds in the human body using decision tree-based regression methods from the area of data mining (or machine learning). Hence, the pros and cons of several different types of decision tree-based regression methods have been discussed. The regression methods predict Vss using, as predictive features, both the compounds’ molecular descriptors and the compounds’ tissue:plasma partition coefficients (Kt:p) – often used in physiologically-based pharmacokinetics. Therefore, this work has assessed whether the data mining-based prediction of Vss can be made more accurate by using as input not only the compounds’ molecular descriptors but also (a subset of) their predicted Kt:p values.

Results

Comparison of the models that used only molecular descriptors, in particular, the Bagging decision tree (mean fold error of 2.33), with those employing predicted Kt:p values in addition to the molecular descriptors, such as the Bagging decision tree using adipose Kt:p (mean fold error of 2.29), indicated that the use of predicted Kt:p values as descriptors may be beneficial for accurate prediction of Vss using decision trees if prior feature selection is applied.

Conclusions

Decision tree based models presented in this work have an accuracy that is reasonable and similar to the accuracy of reported Vss inter-species extrapolations in the literature. The estimation of Vss for new compounds in drug discovery will benefit from methods that are able to integrate large and varied sources of data and flexible non-linear data mining methods such as decision trees, which can produce interpretable models.
Understanding the MIND phenotype: macrophage/microglia inflammation in neurocognitive disorders related to human immunodeficiency virus infection
Authors: Brown Amanda
Published: February 2015

Tissue macrophages play important roles in maintaining homeostasis in most organs of the body including the brain where microglia represent the resident phagocytic cells of this compartment. The possibility of one day harnessing macrophage plasticity to treat or ameliorate disorders including obesity, cancer, organ damage, intestinal disorders, neurodegeneration, and cardiovascular disease in which these cells play a role, is a very exciting prospect. Inflammatory signaling is required for regenerative repair, healing, and pathogen clearance functions. However, when the inflammatory response persists in a chronic fashion over an extended period of time, damage to neurons is followed by neuronal injury and dysfunction. Macrophages in the brain are heterogeneous arising from tissues during embryogenesis, and in the adult, from bone marrow derived monocytes that enter through the blood–brain‐barrier. While much of our insight regarding macrophage functional subtypes has been garnered through elegant studies in mice, which are amenable to genetic manipulation, far less is known about such cells in human tissues, and particularly in the brain under normal, disease, or injurious conditions. In this regard, non‐human primate models for human immunodeficiency virus have been extremely useful for understanding the contribution of bone marrow‐derived monocytes in neurological disease and their interaction and impact on the activation state of resident microglia in the brain. This review will focus on what has been learned from the rhesus macaque models about the types of macrophages present in the brains of animals with encephalitis. In vitro studies, which have used human blood monocytes differentiated into macrophages to address the question of macrophage subsets in HIV infection will be highlighted. Recent insights on macrophage phenotype and persistent inflammation in the brain in HIV‐associated neurocognitive disorder from immunohistochemical studies on human autopsy tissue will be examined.
Thermographic inspection of cracks in the mixed materials statue: Ratto delle Sabine
Authors: Di Tuccio Maria C , Ludwig Nicola , Gargano Marco , Bernardi Adriana
Published: February 2015

This work describes a simple use of active Infrared Thermography developed to detect the level of weathering of a statue with respect to cracks observed on the surface. The statue “Ratto delle Sabine” of Giambologna is exposed in the Galleria of the Accademia in Florence-Italy and was the object onto which the methodology of analysis was used. Radiographic analyses indicated that the statue was originally made out of composite materials (mainly wood and tissue at the inner part and raw clay at the outer part). This artefact is a model which was originally not conceived to last for a long time and nowadays shows severe cracks. Thermal investigations have been done in laboratory and in field to evaluate the level of weathering of the statue, in particular related to the previously mentioned cracks. The main purpose of this study was to find a way to detect and/or demonstrate eventual interconnections between the different cracks and to evaluate the state of weathering of the statue. The methodology is based on insufflating hot air locally into the cracks of the statue during a short time, monitoring at the same time the surface temperature evolution near to the place of inflow and observing if the hot air emerges at the opposite side.

To assess the eventual danger of this methodology of blowing in hot air locally, preliminary tests were made in laboratory using samples composed out of different combinations of materials (raw clay, wood, tissue, etc.) similar to the ones composing the statue. Such tests have shown that a heating time of a few minutes was sufficient to highlight the leaking of warm air from the inflow opening to the back side and this without an excessive temperature increase of the surface near the infiltration point. This was done respecting the conservation restrictions and rules for the these materials. Results in lab and field demonstrated the potential efficiency of the method to monitor the conservation state of this fragile artefact. In this specific application the method allowed to identify four critical points in the “Ratto delle Sabine” model.
Application of Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry in the Screening of VanA-Positive Enterococcus Faecium
Authors: Wei Wu , Li-Jun Wang , Wen-Jun Sui , Gui Zhang , Xin-Xin Lu
Published: February 2015

In order to evaluate a rapid matrix-assisted laser desorption ionization-time of flight mass spectrometry (MAIDI-TOF MS) assay in screening vancomycin-resistant Enterococcus faecium, a total of 150 E. faecium clinical strains were studied, including 60 vancomycin-resistant E. faecium (VREF) isolates and 90 vancomycin-susceptible (VSEF) strains. Vancomycin resistance genes were detected by sequencing. E. faecium were identified by MALDI-TOF MS. A genetic algorithm model with ClinProTools software was generated using the spectra of 30 VREF isolates and 30 VSEF isolates. Using this model, 90 test isolates were discriminated between VREF and VSEF. The results show that all 60 VREF isolates carried the vanA gene. The performance of VREF detection by the genetic algorithm model of MALDI-TOF MS compared to the sequencing method was: sensitivity = 80%, specificity = 90%, false-positive rate = 10%, false-negative rate = 10%, positive predictive value = 80%, negative predictive value = 90%. MALDI-TOF MS can be used as a screening test for discrimination between vanA-positive E. faecium and vanA-negative E. faecium.
Management of bulbar symptoms in motor neurone disease: a community speech and language therapist perspective
Authors: Barber Camilla
Published: February 2015

Motor neurone disease (MND) is a neurodegenerative condition that leads to progressive weakness of the limbs, bulbar and respiratory muscles. The speech and language therapist (SLT), alongside the wider multidisciplinary team, can play a key role in managing bulbar symptoms associated with MND. This article provides an overview of speech and swallowing difficulties associated with MND and the possible management options.
Politics and palliative care: Cuba
Authors: Smyth Dion
Published: February 2015

Dion Smyth's review of the internet for palliative nursing
The person behind the patient: a feasibility study using the Patient Dignity Question for patients with palliative care needs in hospital
Authors: Johnston Bridget , Gaffney Marion , Pringle Jan , Buchanan Deans
Published: February 2015

Objective:

The purpose of this study was to assess the feasibility and acceptability of the Patient Dignity Question (PDQ) ‘what do I need to know about you as a person to take the best care of you that I can?’, as a person-centred intervention for patients with palliative needs in the acute hospital setting in Scotland, UK.

Method:

To test the feasibility of the research design, a purposive sample of nine patients and five health-care professionals (HCPs) were recruited from acute wards in the east of Scotland. Responses to the PDQ were assessed using a PDQ feedback questionnaire to gauge participant reaction to its use. A person-centred climate questionnaire (PCQ-P) was used to assess responses to the environment in relation to the person-centred approach.

Results:

The results from responses to the PDQ feedback questionnaire indicate that it is feasible to carry out this type of study for people with palliative care needs in the acute care setting, and that participants found the PDQ acceptable. The PCQ-P was effective in determining the person-centred nature of the hospital climate. However, it was not possible to determine if the PDQ had a direct influence on this, without pre- and post-intervention data.

Conclusions:

The PDQ was feasible and acceptable for this group of participants as a means by which HCPs may enhance person-centred care for people with palliative needs in an acute hospital. Testing the implementation of the PDQ in a before-and-after study would be beneficial.