Editorial Board/Aims and Scope

Publication date: 4 November 2015
Source:Vaccine, Volume 33, Issue 44





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Prospective on multiscale simulation of virus-like particles: Application to computer-aided vaccine design

Publication date: 4 November 2015
Source:Vaccine, Volume 33, Issue 44
Author(s): Andrew Abi Mansour, Yuriy V. Sereda, Jing Yang, Peter J. Ortoleva
Simulations of virus-like particles needed for computer-aided vaccine design highlight the need for new algorithms that accelerate molecular dynamics. Such simulations via conventional molecular dynamics present a practical challenge due to the millions of atoms involved and the long timescales of the phenomena of interest. These phenomena include structural transitions, self-assembly, and interaction with a cell surface. A promising approach for addressing this challenge is multiscale factorization. The approach is distinct from coarse-graining techniques in that it (1) avoids the need for conjecturing phenomenological governing equations for coarse-grained variables, (2) provides simulations with atomic resolution, (3) captures the cross-talk between disturbances at the atomic and the whole virus-like particle scale, and (4) achieves significant speedup over molecular dynamics. A brief review of multiscale factorization method is provided, as is a prospective on its development.



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Soluble Urokinase Receptor and Chronic Kidney Disease

Chronic kidney disease and progressive loss of kidney function constitute a major public health problem affecting 11% of the U.S. population. Patients with chronic kidney disease are at high risk for cardiovascular disease and death. It is thus important to identify patients at high risk for…

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Influence of Serum and Hypoxia on Incorporation of [ 14 C]- d -Glucose or [ 14 C]- l -Glutamine into Lipids and Lactate in Murine Glioblastoma Cells

Abstract

Glucose and glutamine are essential energy metabolites for brain tumor growth and survival under both normoxic and hypoxic conditions. Both metabolites can contribute their carbons to lipid biosynthesis. We used uniformly labeled [¹⁴C]-U-d-glucose and [¹⁴C]-U-l-glutamine to examine the profile of de novo lipid biosynthesis in the VM-M3 murine glioblastoma cells. The major lipids synthesized included phosphatidylcholine (PtdCho), phosphatidylethanolamine (EtnGpl), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer), sphingomyelin (CerPCho), bis(monoacylglycero)phosphate (BMP)/phosphatidic acid (PtdOH), cholesterol (C), cardiolipin (Ptd₂Gro), and gangliosides. Endogenous lipid synthesis, using either glucose or glutamine, was greater in media without fetal bovine serum (FBS) than in media containing 10 % FBS under normoxia. De novo lipid synthesis was greater using glucose carbons than glutamine carbons under normoxia. The reverse was observed for most lipids under hypoxia suggesting an attenuation of glucose entering the TCA cycle. Lactate was produced largely from glucose carbons with minimal lactate derived from glutamine under either normoxia or hypoxia. Accumulation of triacylglycerols (TAG), containing mostly saturated and mono-unsaturated fatty acids, was observed under hypoxia using carbons from either glucose or glutamine. The data show that the incorporation of labeled glucose and glutamine into most synthesized lipids was dependent on the type of growth environment, and that the VM-M3 glioblastoma cells could acquire lipids, especially cholesterol, from the external environment for growth and proliferation.

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Dietary ALA from Spinach Enhances Liver n-3 Fatty Acid Content to Greater Extent than Linseed Oil in Mice Fed Equivalent Amounts of ALA

Abstract

Although several works have reported absorption rate differences of n-3 polyunsaturated fatty acids (PUFA) bound to different lipid forms, such as ethyl ester, triacylglycerol (TAG), and phospholipids, no studies have investigated the effect of n-3 PUFA from glycolipids (GL). The present study compared the fatty acid contents of tissue and serum lipids from normal C57BL/6J mice fed two types of α-linolenic acid (ALA)-rich lipids, spinach lipid (SPL), and linseed oil (LO). ALA was primarily present as the GL form in SPL, while it existed as TAG in LO. Supplementation of both lipids increased ALA and its n-3 metabolites, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid, and decreased n-6 PUFA, linoleic acid and arachidonic acid, in the livers, small intestines, and sera of the treated mice compared with those of the control group. When the comparison between the SPL and LO diets containing the same amount of ALA was conducted, the EPA and DPA levels in the liver lipids from mice fed the SPL diet were significantly higher than those fed the LO diet. Additionally, the total contents of n-3 PUFA of lipids from the livers, small intestines, and sera of the SPL group were higher than those of the LO group.

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Two stages of XRCC1 recruitment and two classes of XRCC1 foci formed in response to low level DNA damage induced by visible light, or stress triggered by heat shock

Publication date: Available online 2 November 2015
Source:DNA Repair
Author(s): Kamil J. Solarczyk, Magdalena Kordon, Krzysztof Berniak, Jurek W. Dobrucki
Induction of local photosensitised DNA damage has been used to study recruitment of repair factors, spatial organisation and subsequent stages of the repair processes. However, the damage induced by a focused laser beam interacting with a photosensitiser may not fully reflect the types of damage and repair encountered in cells of an animal under typical conditions in vivo. We report on two characteristic stages of recruitment of XRCC1 (a protein engaged in BER and SSB repair pathways), in response to low level DNA damage induced by visible light. We demonstrate that, when just a few DNA breaks are induced in a small region of the nucleus, the recruited XRCC1 is initially distributed uniformly throughout this region, and rearranges into several small stationary foci within minutes. In contrast, when heavy damage of various types (including oxidative damage) is induced in cells pre-sensitized with a DNA-binding drug ethidium bromide, XRCC1 is also recruited but fails to rearrange from the stage of the uniform distribution to the stage of several small foci, indicating that this heavy damage interferes with the progress and completion of the repair processes. We hypothesize that that first stage may reflect recruitment of XRCC1 to poly(ADP-ribose) moieties in the region surrounding the single-strand break, while the second - binding directly to the DNA lesions. We also show that moderate damage or stress induces formation of two types of XRCC1-containing foci differing in their mobility. A large subset of DNA damage-induced XRCC1 foci is associated with a major component of PML nuclear bodies - the Sp100 protein.



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Modulation of DNA damage responseand induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells

Publication date: Available online 4 November 2015
Source:DNA Repair
Author(s): Raafat A. El-Awady, Mohammad H. Semreen, Maha M. Saber, Farhan Cyprian, Varsha Menon, Taleb H. Al-Tel
DNA damage response machinery (DDR) is an attractive target of cancer therapy. Modulation of DDR network may alter the response of cancer cells to DNA damaging anticancer drugs such as doxorubicin. The aim of the present study is to investigate the effects of a newly developed imidazopyridine (IAZP) derivative on the DDR after induction of DNA damage in cancer cells by doxorubicin. Cytotoxicity sulphrhodamine-B assay showedaweak anti-proliferative effect of IAZP alone on six cancer cell lines (MCF7, A549,A549DOX11,HepG2, HeLa and M8) and a normal fibroblast strain. Combination of IAZP with doxorubicin resulted in synergism in lung (A549) and breast (MCF7) cancer cells but neither in the other cancer cell lines nor in normal fibroblasts. Molecular studies revealed that synergism is mediated by modulation of DNA damage response and induction of apoptosis. Using constant-field gel electrophoresis and immunofluorescence detection of γ–H2AX foci, IAZP was shown to inhibit the repair of doxorubicin-induced DNA damage in A549 and MCF7 cells. Immunoblot analysis showed that IAZP suppresses the phosphorylation of the ataxia lelangiectasia and Rad3 related (ATR) protein, which is an important player in the response of cancer cells to chemotherapy-induced DNA damage.Moreover, IAZP augmented the doxorubicin-induced degradation of p21, activation of p53, CDK2, caspase 3/7 and phosphorylation of Rb protein. These effects enhanced doxorubicin-induced apoptosisin both cell lines. Our results indicate that IAZP is a promising agent that may enhance the cytotoxic effects of doxorubicin on some cancer cells through targeting the DDR. It is a preliminary step toward the clinical application of IAZP in combination with anticancer drugs and opens the avenue for the development of compounds targeting the DDR pathway that might improve the therapeutic index of anticancer drugs and enhance their cure rate.



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Cadmium treatment suppresses DNA polymerase δ catalytic subunit gene expression by acting on the p53 and Sp1 regulatory axis

Publication date: November 2015
Source:DNA Repair, Volume 35
Author(s): Giulia Antoniali, Federica Marcuzzi, Elena Casarano, Gianluca Tell
Cadmium (Cd) is a carcinogenic and neurotoxic environmental pollutant. Among the proposed mechanisms for Cd toxic effects, its ability to promote oxidative stress and to inhibit, in vitro, the activities of some Base Excision DNA Repair (BER) enzymes, such as hOGG1, XRCC1 and APE1, have been already established. However, the molecular mechanisms at the basis of these processes are largely unknown especially at sub-lethal doses of Cd and no information is available on the effect of Cd on the expression levels of BER enzymes. Here, we show that non-toxic treatment of neuronal cell lines, with pro-mitogenic doses of Cd, promotes a significant time- and dose-dependent down-regulation of DNA polymerase δ (POLD1) expression through a transcriptional mechanism with a modest effect on Polβ, XRCC1 and APE1. We further elucidated that the observed transcriptional repression on Polδ is acted by through competition by activated p53 on Sp1 at POLD1 promoter and by a squelching effect. We further proved the positive effect of Sp1 not only on POLD1 expression but also on Polβ, XRCC1 and APE1 expression, suggesting that Sp1 has pleiotropic effects on the whole BER pathway. Our results indicated that Cd-mediated impairment of BER pathway, besides acting on the enzymatic functions of some key proteins, is also exerted at the gene expression level of Polδ by acting on the p53–Sp1 regulatory axis. These data may explain not only the Cd-induced neurotoxic effects but also the potential carcinogenicity of this heavy metal.



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Versatility in phospho-dependent molecular recognition of the XRCC1 and XRCC4 DNA-damage scaffolds by aprataxin-family FHA domains

Publication date: November 2015
Source:DNA Repair, Volume 35
Author(s): Amy L. Cherry, Timothy J. Nott, Geoffrey Kelly, Stuart L. Rulten, Keith W. Caldecott, Stephen J. Smerdon
Aprataxin, aprataxin and PNKP-like factor (APLF) and polynucleotide kinase phosphatase (PNKP) are key DNA-repair proteins with diverse functions but which all contain a homologous forkhead-associated (FHA) domain. Their primary binding targets are casein kinase 2-phosphorylated forms of the XRCC1 and XRCC4 scaffold molecules which respectively coordinate single-stranded and double-stranded DNA break repair pathways. Here, we present the high-resolution X-ray structure of a complex of phosphorylated XRCC4 with APLF, the most divergent of the three FHA domain family members. This, combined with NMR and biochemical analysis of aprataxin and APLF binding to singly and multiply-phosphorylated forms of XRCC1 and XRCC4, and comparison with PNKP reveals a pattern of distinct but overlapping binding specificities that are differentially modulated by multi-site phosphorylation. Together, our data illuminate important differences between activities of the three phospho-binding domains, in spite of a close evolutionary relationship between them.



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Role of mismatch repair proteins in the processing of cisplatin interstrand cross-links

Publication date: November 2015
Source:DNA Repair, Volume 35
Author(s): Akshada Sawant, Anbarasi Kothandapani, Anatoly Zhitkovich, Robert W. Sobol, Steve M. Patrick
Mismatch repair (MMR) deficiency gives rise to cisplatin resistance and can lead to poor prognosis in cancers. Various models have been proposed to explain this low level of resistance caused due to loss of MMR proteins. We have shown that MMR proteins are required to maintain cisplatin interstrand cross-links (ICLs) on the DNA leading to increased cellular sensitivity. In our previous studies, we have shown that BER processing of the cisplatin ICLs is mutagenic. Polymerase β (Polβ) can generate mismatches which leads to the activation and the recruitment of mismatch repair proteins. In this paper, we distinguished between the requirement of different downstream MMR proteins for maintaining cisplatin sensitivity. We show that the MutSα (MSH2–MSH6) heterocomplex is required to maintain cisplatin sensitivity, whereas the Mutsβ complex has no effect. These results can be correlated with the increased repair of cisplatin ICLs and ICL induced DNA double strand breaks (DSBs) in the resistant cells. Moreover, we show that MLH1 proficient cells displayed a cisplatin sensitive phenotype when compared with the MLH1 deficient cells and the ATPase activity of MLH1 is essential to mediate this effect. Based on these results, we propose that MutSα as well as the downstream MMR pathway proteins are essential to maintain a cisplatin sensitive phenotype as a consequence of processing Polβ induced mismatches at sites flanking cisplatin ICLs.



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In vitro chromatin templates to study nucleotide excision repair

Publication date: Available online 22 October 2015
Source:DNA Repair
Author(s): Xiaoqi Liu
In eukaryotic cells, DNA associates with histones and exists in the form of a chromatin hierarchy. Thus, it is generally believed that many eukaryotic cellular DNA processing events such as replication, transcription, recombination and DNA repair are influenced by the packaging of DNA into chromatin. This mini-review covers the current knowledge of DNA damage and repair in chromatin based on in vitro studies. Specifically, nucleosome assembly affects DNA damage formation in both random sequences and sequences with strong nucleosome-positioning signals such as 5S rDNA. At least three systems have been used to analyze the effect of nucleosome folding on nucleotide excision repair (NER) in vitro: (a) human cell extracts that have to rely on labeling of repair synthesis to monitor DNA repair, due to very low repair efficacy; (b) Xenopus oocyte nuclear extracts, that have very robust DNA repair efficacy, have been utilized to follow direct removal of DNA damage; (c) six purified human DNA repair factors (RPA, XPA, XPC, TFIIH, XPG, and XPF-ERCC1) that have been used to reconstitute excision repair in vitro. In general, the results have shown that nucleosome folding inhibits NER and, therefore, its activity must be enhanced by chromatin remodeling factors like SWI/SNF. In addition, binding of transcription factors such as TFIIIA to the 5S rDNA promoter also modulates NER efficacy.



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Historical perspective on the DNA damage response

Publication date: Available online 22 October 2015
Source:DNA Repair
Author(s): Philip C. Hanawalt
The DNA damage response (DDR) has been broadly defined as a complex network of cellular pathways that cooperate to sense and repair lesions in DNA. Multiple types of DNA damage, some natural DNA sequences, nucleotide pool deficiencies and collisions with transcription complexes can cause replication arrest to elicit the DDR. However, in practice, the term DDR as applied to eukaryotic/mammalian cells often refers more specifically to pathways involving the activation of the ATM (ataxia-telangiectasia mutated) and ATR (ATM-Rad3-related) kinases in response to double-strand breaks or arrested replication forks, respectively. Nevertheless, there are distinct responses to particular types of DNA damage that do not involve ATM or ATR. In addition, some of the aberrations that cause replication arrest and elicit the DDR cannot be categorized as direct DNA damage. These include nucleotide pool deficiencies, nucleotide sequences that can adopt non-canonical DNA structures, and collisions between replication forks and transcription complexes. The response to these aberrations can be called the genomic stress response (GSR), a term that is meant to encompass the sensing of all types of DNA aberrations together with the mechanisms involved in coping with them. In addition to fully functional cells, the consequences of processing genomic aberrations may include mutagenesis, genomic rearrangements and lethality.



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Evelyn Witkin and the Coordinated Response to DNA Damage

Publication date: Available online 21 October 2015
Source:DNA Repair
Author(s): Joann B. Sweasy, Howard B. Lieberman, Michael Volkert, Donna George




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Design, synthesis, and characterization of nucleosomes containing site-specific DNA damage

Publication date: Available online 19 October 2015
Source:DNA Repair
Author(s): John-Stephen Taylor
How DNA damaged is formed, recognized, and repaired in chromatin is an area of intense study. To better understand the structure activity relationships of damaged chromatin, mono and dinucleosomes containing site-specific damage have been prepared and studied. This review will focus on the design, synthesis, and characterization of model systems of damaged chromatin for structural, physical, and enzymatic studies.

Graphical abstract

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Evaluation of leishmanicidal activity and cytotoxicity of Ricinus communis and Azadirachta indica extracts from western Kenya: in vitro and in vivo assays

Background: Despite advances to targeted leishmanicidal chemotherapy, defies around severe toxicity, recent emergence of resistant variants and absence of rational vaccine still persist. This necessitates search and/or progressive validation of accessible medicinal remedies including plant based. The study examined both in vivo and in vitro response of L. major infection to combined therapy of Ricinus communis and Azadirachta indica extracts in BALB/c mice as the mouse model. A comparative study design was applied. Results: BALB/c mice, treated with combination therapy resulted in significantly (p < 0.05) larger reduction of lesion than those treated with monotherapies. The spleno-somatic index was found to be significantly low with combination therapy than monotherapies. Antiparasitic effect of A. indica and R. communis on amastigote with a 50 % inhibitory concentration (IC 50 ) was of 11.5 and 16.5 µg mL −1 respectively while combination therapy gave 9.0 µg ml −1 compared to the standard drugs, Pentostam and amphotericin B which had an IC 50 of 6.5 and 4.5 µg ml −1 respectively. Optimal efficacy of A. indica and R. communis was 72 and 59.5 % respectively, combination therapy gave 88 %, while Pentostam and amphotericin B had 98 and 92 % respectively against amastigotes. Against promastigotes A. indica and R. Communis gave an IC 50 of 10.1, 25.5 µg mL −1 respectively, while combination, 12.2 µg mL −1 against 4.1 and 5.0 µg ml −1 for Pentostam and amphotericin B respectively. The optimal efficacy of the compounds against promastigotes was 78.0, 61.5 and 91.2 % (A. indica, R. communis and A. indica + R. communis respectively) against 96.5 and 98 % for Pentostam and amphotericin B respectively. The concentrations at optimal efficacy were significantly different (p < 0.05) among the test compounds. An evaluation of the IC 50 values of the combination therapies clearly reveals synergistic effects. Conclusion: Combination therapy of A. indica and R. communis had best antileishmanial activity than the monotherapies. The active ingredients of both R. communis and A. indica need to be fractionated, and studied further for activity against Leishmania parasites.

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Prevalence of intestinal parasites among patients of a Ghanaian psychiatry hospital

Background: Neglected tropical diseases are of major concern to sub-Saharan African countries. Though efforts to monitor the prevalence and control are in place, these are mostly restricted to groups within the population. This study was performed to determine the prevalence among patients of a Ghanaian psychiatric hospital and find out whether there is a reason for active monitoring in this population. Methods: A cross-sectional study was performed to determine the prevalence of intestinal parasites among patients of a Ghanaian psychiatric hospital. Stool samples were collected and analyzed in addition to data. Results: Of the 111 patients studied, asymptomatic carriage of parasites was 13.5 % and was higher in males (18.8 %) than in females (4.8 %). Carriage of parasites decreased with age but increase with duration of admission. Conclusion: This is the first report of parasitic pathogens among patients of a psychiatric institution in Ghana. The data shows that there are risks of transmission of infectious diseases via the oral route hence, the need for regular monitoring and intervention is emphasized.

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Photolithographic Synthesis of High-Density DNA and RNA Arrays on Flexible, Transparent, and Easily Subdivided Plastic Substrates

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b02893

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Tracking the Invasion of Small Numbers of Cells in Paper-Based Assays with Quantitative PCR

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b02362

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Elasto-Inertial Pinched Flow Fractionation for Continuous Shape-Based Particle Separation

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b03321

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Conditions Affecting Social Space in Drosophila melanogaster

The effect of genes and environment on social space of Drosophila melanogaster can be quantified through a powerful but straightforward analytical paradigm. We show here different factors that can affect this social space, and thus need to be taken into consideration when designing experiments in this paradigm.

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Synthesis and Functionalization of 3D Nano-graphene Materials: Graphene Aerogels and Graphene Macro Assemblies

This video method describes the synthesis of high surface area, monolithic 3D graphene-based materials derived from polymer precursors as well as single layer graphene oxide.

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Preventing ICU Subsyndromal Delirium Conversion to Delirium With Low-Dose IV Haloperidol: A Double-Blind, Placebo-Controlled Pilot Study.

Objective: To compare the efficacy and safety of scheduled low-dose haloperidol versus placebo for the prevention of delirium (Intensive Care Delirium Screening Checklist >= 4) administered to critically ill adults with subsyndromal delirium (Intensive Care Delirium Screening Checklist = 1-3). Design: Randomized, double-blind, placebo-controlled trial. Setting: Three 10-bed ICUs (two medical and one surgical) at an academic medical center in the United States. Patients: Sixty-eight mechanically ventilated patients with subsyndromal delirium without complicating neurologic conditions, cardiac surgery, or requiring deep sedation. Interventions: Patients were randomly assigned to receive IV haloperidol 1 mg or placebo every 6 hours until delirium occurred (Intensive Care Delirium Screening Checklist >= 4 with psychiatric confirmation), 10 days of therapy had elapsed, or ICU discharge. Measurements and Main Results: Baseline characteristics were similar between the haloperidol (n = 34) and placebo (n = 34) groups. A similar number of patients given haloperidol (12/34 [35%]) and placebo (8/34 [23%]) developed delirium (p = 0.29). Haloperidol use reduced the hours per study day spent agitated (Sedation Agitation Scale >= 5) (p = 0.008), but it did not influence the proportion of 12-hour ICU shifts patients spent alive without coma (Sedation Agitation Scale

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Economic Evaluation of Telemedicine for Patients in ICUs.

Objective: Despite telemedicine's potential to improve patients' health outcomes and reduce costs in the ICU, hospitals have been slow to introduce telemedicine in the ICU due to high up-front costs and mixed evidence on effectiveness. This study's first aim was to conduct a cost-effectiveness analysis to estimate the incremental cost-effectiveness ratio of telemedicine in the ICU, compared with ICU without telemedicine, from the healthcare system perspective. The second aim was to examine potential cost saving of telemedicine in the ICU through probabilistic analyses and break-even analyses. Design: Simulation analyses performed by standard decision models. Setting: Hypothetical ICU defined by the U.S. literature. Patients: Hypothetical adult patients in ICU defined by the U.S. literature. Interventions: The intervention was the introduction of telemedicine in the ICU, which was assumed to affect per-patient per-hospital-stay ICU cost and hospital mortality. Telemedicine in the ICU operation costs included the telemedicine equipment-installation (start-up) costs with 5-year depreciation, maintenance costs, and clinician staffing costs. Telemedicine in the ICU effectiveness was measured by cumulative quality-adjusted life years for 5 years after ICU discharge. Measurements and Main Results: The base case cost-effectiveness analysis estimated telemedicine in the ICU to extend 0.011 quality-adjusted life years with an incremental cost of $516 per patient compared with ICU without telemedicine, resulting in an incremental cost-effectiveness ratio of $45,320 per additional quality-adjusted life year (= $516/0.011). The probabilistic cost-effectiveness analysis estimated an incremental cost-effectiveness ratio of $50,265 with a wide 95% CI from a negative value (suggesting cost savings) to $375,870. These probabilistic analyses projected that cost saving is achieved 37% of 1,000 iterations. Cost saving is also feasible if the per-patient per-hospital-stay operational cost and physician cost were less than $422 and less than $155, respectively, based on break-even analyses. Conclusions: Our analyses suggest that telemedicine in the ICU is cost-effective in most cases and cost saving in some cases. The thresholds of cost and effectiveness, estimated by break-even analyses, help hospitals determine the impact of telemedicine in the ICU and potential cost saving. Copyright (C) by 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Comparison Between Neurally Adjusted Ventilatory Assist and Pressure Support Ventilation Levels in Terms of Respiratory Effort.

Objectives: To understand the potential equivalence between neurally adjusted ventilatory assist and pressure support ventilation levels in terms of respiratory muscle unloading. To compare the respiratory pattern, variability, synchronization, and neuromuscular coupling within comparable ranges of assistance. Design: Prospective single-center physiologic study. Setting: A 13-bed university medical ICU. Patients: Eleven patients recovering from respiratory failure. Interventions: The following levels of assistance were consecutively applied in a random order: neurally adjusted ventilatory assist levels: 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 7 cm H2O/[mu]volt; pressure support levels: 7, 10, 15, 20, and 25 cm H2O. Measurements and Main Results: Flow, airway pressure, esophageal pressures, and peak electrical activity of the diaphragm were continuously recorded. Breathing effort was calculated. To express the percentage of assist assumed by the ventilator, the total pressure including muscular and ventilator pressure was calculated. The median percentage of assist ranged from 33% (24-47%) to 82% (72-90%) between pressure support 7 and 25 cm H2O. Similar levels of unloading were observed for neurally adjusted ventilatory assist levels from 0.5 cm H2O/[mu]volt (46% [40-51%]) to 2.5 cm H2O/[mu]volt (80% [74-84%]). Tidal variability was higher during neurally adjusted ventilatory assist and ineffective efforts appeared only in pressure support. In neurally adjusted ventilatory assist, double triggering occurred sometimes when electrical activity of the diaphragm signal depicted a biphasic aspect, and an abnormal oscillatory pattern was frequently observed from 4 cm H2O/[mu]volt. For both modes, the relationship between peak electrical activity of the diaphragm and muscle pressure depicted a curvilinear profile. Conclusions: In patients recovering from acute respiratory failure, levels of neurally adjusted ventilatory assist between 0.5 and 2.5 cm H2O/[mu]volt are comparable to pressure support levels ranging from 7 to 25 cm H2O in terms of respiratory muscle unloading. Neurally adjusted ventilatory assist provides better patient-ventilator interactions but can be sometimes excessively sensitive to electrical activity of the diaphragm in terms of triggering. Copyright (C) by 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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A Dysregulated Balance of Proinflammatory and Anti-Inflammatory Host Cytokine Response Early During Therapy Predicts Persistence and Mortality in Staphylococcus aureus Bacteremia.

Objectives: The contribution of individual immune response to Staphylococcus aureus bacteremia on outcome has not been well studied. The objective was to relate the host cytokine response to outcome of Staphylococcus aureus bacteremia. Design: Prospective observational study. Setting: Three U.S. university-affiliated medical centers. Patients: Adult patients infected with Staphylococcus aureus bacteremia hospitalized between July 2012 and August 2014. Interventions: Blood specimens were obtained at Staphylococcus aureus bacteremia onset and 72 hours after therapy initiation. Levels of tissue necrosis factor, interleukin-6, interleukin-8, interleukin-17A, and interleukin-10 were measured by enzyme-linked immunosorbent assay at each time point and compared between those with persistent bacteremia (>= 4 d) and resolving bacteremia. Primary outcome was persistent bacteremia after 4 days of effective therapy. Secondary outcomes were 30-day mortality and 30-day recurrence. Measurements and Main Results: A total of 196 patients were included (mean age, 59 yr); of them, 33% had methicillin-resistant Staphylococcus aureus bacteremia. Forty-seven percent of the methicillin-resistant Staphylococcus aureus strains were staphylococcal cassette chromosome mec IV. Persistent bacteremia occurred in 24% of patients (47/196); they were more likely to die than resolving bacteremia group (28% vs 5%; p

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Interleukin-17A Is Associated With Alveolar Inflammation and Poor Outcomes in Acute Respiratory Distress Syndrome.

Objective: Interleukin-17A is a proinflammatory cytokine known to play a role in host defense and pathologic inflammation in murine models of lung injury. The relationship between interleukin-17A and inflammation in human lung injury is unknown. Our primary objective was to determine whether interleukin-17A levels are associated with alveolar measures of inflammation and injury in patients with acute respiratory distress syndrome. Our secondary objective was to test whether interleukin-17A levels are associated with acute respiratory distress syndrome-related outcomes. Design: Observational study. Setting: Six North American medical centers. Patients: We studied two groups of patients with acute respiratory distress syndrome: 1) patients previously enrolled in a placebo-controlled clinical trial of omega-3 fatty acids performed at five North American medical centers (n = 86, acute respiratory distress syndrome 1), and 2) patients with systemic inflammatory response syndrome admitted to an ICU who developed acute respiratory distress syndrome (n = 140, acute respiratory distress syndrome 2). In acute respiratory distress syndrome 1, we used paired serum and bronchoalveolar lavage fluid samples obtained within 48 hours of acute respiratory distress syndrome onset, whereas in acute respiratory distress syndrome 2, we used plasma obtained within the first 24 hours of ICU admission. Interventions: None. Measurements and Main Results: We measured circulating interleukin-17A in acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2. We also measured interleukin-17A, neutrophil counts, and total protein in bronchoalveolar lavage fluid from acute respiratory distress syndrome 1. We found that bronchoalveolar lavage interleukin-17A was strongly associated with higher bronchoalveolar lavage percent neutrophils (p

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Evaluation Following Staggered Implementation of the "Rethinking Critical Care" ICU Care Bundle in a Multicenter Community Setting.

Objectives: To evaluate process metrics and outcomes after implementation of the "Rethinking Critical Care" ICU care bundle in a community setting. Design: Retrospective interrupted time-series analysis. Setting: Three hospitals in the Kaiser Permanente Northern California integrated healthcare delivery system. Patients: ICU patients admitted between January 1, 2009, and August 30, 2013. Interventions: Implementation of the Rethinking Critical Care ICU care bundle which is designed to reduce potentially preventable complications by focusing on the management of delirium, sedation, mechanical ventilation, mobility, ambulation, and coordinated care. Rethinking Critical Care implementation occurred in a staggered fashion between October 2011 and November 2012. Measurements and Main Results: We measured implementation metrics based on electronic medical record data and evaluated the impact of implementation on mortality with multivariable regression models for 24,886 first ICU episodes in 19,872 patients. After implementation, some process metrics (e.g., ventilation start and stop times) were achieved at high rates, whereas others (e.g., ambulation distance), available late in the study period, showed steep increases in compliance. Unadjusted mortality decreased from 12.3% to 10.9% (p

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The Effect of Dexamethasone on Symptoms of Posttraumatic Stress Disorder and Depression After Cardiac Surgery and Intensive Care Admission: Longitudinal Follow-Up of a Randomized Controlled Trial.

Objective: Cardiac surgery and postoperative admission to the ICU may lead to posttraumatic stress disorder and depression. Perioperatively administered corticosteroids potentially alter the risk of development of these psychiatric conditions, by affecting the hypothalamic-pituitary-adrenal axis. However, findings of previous studies are inconsistent. We aimed to assess the effect of a single dose of dexamethasone compared with placebo on symptoms of posttraumatic stress disorder and depression and health-related quality of life after cardiac surgery and ICU admission. Design: Follow-up study of a randomized clinical trial. Setting: Five Dutch heart centers. Patients: Cardiac surgery patients (n = 1,244) who participated in the Dexamethasone for Cardiac Surgery trial. Interventions: A single intraoperative IV dose of dexamethasone or placebo was administered in a randomized, double-blind way. Measurements and Main Results: Symptoms of posttraumatic stress disorder, depression, and health-related quality of life were assessed with validated questionnaires 1.5 years after randomization. Data were available for 1,125 patients (90.4%); of which 561 patients received dexamethasone and 564 patients received placebo. Overall, the prevalence of psychopathology was not influenced by dexamethasone. Posttraumatic stress disorder and depression were present in, respectively, 52 patients (9.3%) and 69 patients (12.3%) who received dexamethasone and in 66 patients (11.7%) and 78 patients (13.8%) who received placebo (posttraumatic stress disorder: odds ratio, 0.82; 95% CI, 0.55-1.20; p = 0.30; depression: odds ratio, 0.92; 95% CI, 0.64-1.31; p = 0.63). Subgroup analysis revealed a lower prevalence of posttraumatic stress disorder (odds ratio, 0.23; 95% CI, 0.07-0.72; p

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Protective Effect of Areca catechu Leaf Ethanol Extract Against Ethanol-Induced Gastric Ulcers in ICR Mice

Journal of Medicinal Food , Vol. 0, No. 0.


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Serum 25-Hydroxyvitamin D and Osteoarthritis in Older People: The Progetto Veneto Anziani Study

Rejuvenation Research , Vol. 0, No. 0.


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Total error vs. measurement uncertainty: revolution or evolution?

Journal Name: Clinical Chemistry and Laboratory Medicine (CCLM)
Issue: Ahead of print


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Selective extraction and determination of fluoroquinolones in bovine milk samples with montmorillonite magnetic molecularly imprinted polymers and capillary electrophoresis

Abstract

A sensitive and selective method for separating fluoroquinolones (FQs) from bovine milk samples was successfully developed using montmorillonite magnetic molecularly imprinted polymers (MMMIPs) as adsorbents. MMMIPs were prepared using montmorillonite as carrier, fleroxacin (FLE) as template molecule, and Fe₃O₄ magnetite as magnetic component. MMMIPs possessed high adsorption capacity of 46.3 mg g⁻¹ for FLE. A rapid and convenient magnetic solid-phase extraction procedure coupled with capillary electrophoresis was established with MMMIPs as adsorbents for simultaneous and selective extraction of four FQs in bovine milk samples. Limits of detection ranged between 12.9 and 18.8 μg L⁻¹, and the RSDs were between 1.8 % and 8.6 %. The proposed method was successfully applied to spike bovine milk samples with recoveries of 92.7 %–108.6 %.

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Assessing similarity analysis of chromatographic fingerprints of Cyclopia subternata extracts as potential screening tool for in vitro glucose utilisation

Abstract

Similarity analysis of the phenolic fingerprints of a large number of aqueous extracts of Cyclopia subternata, obtained by high-performance liquid chromatography (HPLC), was evaluated as a potential tool to screen extracts for relative bioactivity. The assessment was based on the (dis)similarity of their fingerprints to that of a reference active extract of C. subternata, proven to enhance glucose uptake in vitro and in vivo. In vitro testing of extracts, selected as being most similar (n = 5; r ≥ 0.962) and most dissimilar (n = 5; r ≤ 0.688) to the reference active extract, showed that no clear pattern in terms of relative glucose uptake efficacy in C2C12 myocytes emerged, irrespective of the dose. Some of the most dissimilar extracts had higher glucose-lowering activity than the reference active extract. Principal component analysis revealed the major compounds responsible for the most variation within the chromatographic fingerprints, as mangiferin, isomangiferin, iriflophenone-3-C-β-d-glucoside-4-O-β-d-glucoside, iriflophenone-3-C-β-d-glucoside, scolymoside, and phloretin-3′,5′-di-C-β-d-glucoside. Quantitative analysis of the selected extracts showed that the most dissimilar extracts contained the highest mangiferin and isomangiferin levels, whilst the most similar extracts had the highest scolymoside content. These compounds demonstrated similar glucose uptake efficacy in C2C12 myocytes. It can be concluded that (dis)similarity of chromatographic fingerprints of extracts of unknown activity to that of a proven bioactive extract does not necessarily translate to lower or higher bioactivity.

Graphical Abstract

(Dis)similarity of HPLC fingerprints is not predictive of relative in vitro glucos uptake efficacy of C. subternata extracts

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Determination of d -serine in human serum by LC-MS/MS using a triazole-bonded column after pre-column derivatization with ( S )-4-(3-isothiocyanatopyrrolidin-1-yl)-7- ( N , N -dimethylaminosulfonyl)-2,1,3-benzoxadiazole

Abstract

An LC-MS/MS-based method for determining d-serine (Ser), an endogenous co-agonist of the N-methyl-D-aspartate receptor, in human serum, was developed and validated using a triazole-bonded silica-packed column after pre-column fluorescence derivatization with a chiral labeling reagent, (S)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole. Enantiomeric separation of the d- and L-Ser derivatives occurred in the triazole-bonded column (R _s: 1.85) with CH₃CN/100 mM HCO₂NH₄ in H₂O (95.5:4.5) as the mobile phase with isocratic elution. The ln(capacity factor of d-Ser) in the van't Hoff plot gradually decreased with the inverse of temperature, suggesting enhanced hydrophilic interactions with the triazole-bonded stationary phase with increasing column temperature, owing to decrease in the partition coefficient to the mobile phase. Multiple reaction monitoring (m/z 457.10 > 409.00) by triple quadrupole mass spectrometry was used for quantifying d-Ser in human serum. The presence of d-Ser in the serum was confirmed by treatment with commercial d-amino acid oxidase. A linear calibration curve was constructed in the d-Ser concentration range of 0.5–5.0 μM (r ² = 0.999, n = 3) using d-homoserine as the internal standard. The precision and recovery values were adequate for quantification. The detection limit for d-Ser was 1.1 fmol/injection (signal-to-noise ratio = 3), owing to the high CH₃CN content in the mobile phase. The proposed LC-MS/MS method showed few fluctuations in the retention times of D- and L-Ser, and R _s was stable until the 40th injection of serum without column washing, and thus can be useful for d-Ser determination in human serum in clinical research.

Graphical Abstract

Multiple reaction monitoring chromatogram (left) and van't Hoff plot (right) of (S)-DBD-PyNCS-D- and L-serine on triazole-bonded column, obtained by LC-MS/MS

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Determination of Effective Stability Constants of Ion-Carrier Complexes in Ion Selective Nanospheres with Charged Solvatochromic Dyes

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b03526

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Chronic Intermittent Hypoxia and Blood Pressure: Is There Risk for Hypertension in Healthy Individuals?

High Altitude Medicine & Biology , Vol. 0, No. 0.


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IFN-γ Induces Mimic Extracellular Trap Cell Death in Lung Epithelial Cells Through Autophagy-Regulated DNA Damage

Journal of Interferon & Cytokine Research , Vol. 0, No. 0.


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Special Collection: Emerging Concepts in Three-Dimensional Microtissues

Tissue Engineering Part A , Vol. 0, No. 0.


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Serum 25-Hydroxyvitamin D and Osteoarthritis in Older People: The Progetto Veneto Anziani Study

Rejuvenation Research , Vol. 0, No. 0.


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Chronic Intermittent Hypoxia and Blood Pressure: Is There Risk for Hypertension in Healthy Individuals?

High Altitude Medicine & Biology , Vol. 0, No. 0.


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Dielectric Barrier Discharge Ionization of Perfluorinated Compounds

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b03538

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Label-Free and Sensitive Detection of Thrombomodulin, a Marker of Endothelial Cell Injury, Using Quartz Crystal Microbalance

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b02447

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A J-shaped relationship between caloric intake and survival in critically ill patients

Background: There is much controversy around the optimal caloric intake in intensive care unit (ICU) patients, based on the diverging results of prospective studies. Therefore, we assessed the presence of an association between caloric intake and outcome in a large cohort included in the Glucontrol study. Methods: Patients (n = 1004) were divided into four quartiles (q1–q4) according to the daily caloric intake (n = 251/quartile). ICU, hospital and 28-day mortality and the length of stay (LOS) in ICU and in the hospital were compared between each quartile, before and after adjustment in case of differences in baseline characteristics. Results: Caloric intake averaged 0.5 ± 0.6 (q1), 3.0 ± 0.7 (q2), 13.4 ± 5.1 (q3) and 32.4 ± 8.5 (q4) kcal/kg/day (p < 0.001 between quartiles). Comparisons among quartiles revealed that ICU, hospital and 28-day mortality were lower in q2 than in the other quartiles. ICU and hospital LOS were lower in q1 and q2. After adjustment for age, type of admission and severity scores, hospital mortality was lower in q2 than in the other quartiles, and LOS was lower in q1and q2 than in q3–q4. Conclusions: In this large and heterogeneous cohort of ICU short stayers, a J-shaped relationship between the amount of calories provided and outcome was found. These hypothesis generating findings are consistent with the concept of improved clinical outcome by early energy restriction.Trial registration#: ClinicalTrials.gov# NCT00107601, EUDRA-CT Number: 200400391440

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Low Resolution Data-Independent Acquisition in an LTQ-Orbitrap Allows for Simplified and Fully Untargeted Analysis of Histone Modifications

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b03009

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Video 3. Incorrectly Predicted Transitions During Real-Time Ambulation Trials With the Powered Prost

Video 3. Incorrectly Predicted Transitions During Real-Time Ambulation Trials With the Powered Prosthetic Leg. Read the article at: http://bit.ly/1NRMSFr

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Video 2. Correctly Predicted Transitions During Real-Time Ambulation Trials With the Powered Prosthe

Video 2. Correctly Predicted Transitions During Real-Time Ambulation Trials With the Powered Prosthetic Leg. Read the article at: http://bit.ly/1NRMSFr

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Video 1. Ambulation Mode Transitions Using a Powered Prosthetic Leg During Control System Training

Video 1. Ambulation Mode Transitions Using a Powered Prosthetic Leg During Control System Training. Read the article at: http://bit.ly/1NRMSFr

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Ocular Movements, Heel-to-Shin Test, and Gait Assessment in a 64-Year-Old Man With Gait Instability

Neurologic examination of a 64-year-old man with gait instability and diplopia. What would you do next? Read the article at: http://bit.ly/1HtuJck

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Simultaneous Electrodialytic Preconcentration and Speciation of Chromium(III) and Chromium(VI)

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b03464

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Surfactant modulated aggregation induced enhancement of emission (AIEE) - a simple demonstration to maximize sensor activity

Analyst, 2015, Accepted Manuscript
DOI: 10.1039/C5AN01916H, Paper

Ali Mahammad, Rahul Bhowmick, Abu Saleh Musha Islam, Atul Katarkar, Keya Chaudhuri
Abstract A new type of easily synthesizable rhodamine-based chemosensor, L3, with potential NO2 donor atoms selectively and rapidly recognizes Hg2+ ion in presence of all biologically relevant metal ions and...
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