Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis.

Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents.

Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study.

Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine

Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

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FOXP2 Promotes Tumor Proliferation and Metastasis by Targeting GRP78 in Triple-negative Breast Cancer

Background: FOXP2, a member of the forkhead box P (FOXP) family, has been reported to be important in breast cancer. However, its exact mechanisms and pathways remain unclear.

Objective: To investigate the effect of FOXP2 on tumor proliferation and metastasis in triplenegative breast cancer (TNBC) and study its underlying molecular mechanism.

Methods: We first used qRT-PCR to detect FOXP2 expression in TNBC cell lines and tissues. Then we conducted cell proliferation assays, colony formation assays, and transwell assays to analyze the effects of FOXP2 expression in TNBC cells. Mouse xenograft model was performed to further confirm the role of FOXP2 in TNBC. Moreover, we used qRT-PCR and Western blot to access the effect of FOXP2 on GRP78 expression and qRT-PCR to analyze GRP78 expression in TNBC tissues. We conducted IHC analysis to detect both FOXP2 and GRP78 expressions in transplanted tumors and used the correlation analysis to further analyze the link between them.

Results: FOXP2 was found to be highly expressed in TNBC cell lines and tissues. FOXP2 knockdown attenuated the growth and invasiveness of TNBC in vitro as well as tumor progression and metastasis in vivo. Moreover, FOXP2 knockdown downregulated glucose-regulated protein of molecular mass 78 (GRP78) expression in TNBC cells and transplanted tumors. Correlation analysis showed that GRP78 expression was positively associated with FOXP2 expression in TNBC cells.

Conclusion: FOXP2 plays a crucial role in TNBC, partly through modulating GRP78, and could act as a potential target for TNBC treatment.

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DNA Fragmentation, Cell Cycle Arrest, and Docking Study of Novel Bis Spiro-cyclic 2-oxindole of Pyrimido[4,5-b]quinoline-4,6-dione Derivatives Against Breast Carcinoma

Background: Recently, it is reported that heterocycles containing pyrimidoquinoline moiety show a broad spectrum of medicinal and pharmacological properties including anticancer, anti-microbial, anti-inflammatory activities, analgesic and antiviral. In additions, spirocyclicoxindole containing compounds represent an important class of compounds that exhibit wide range of biological properties. The asymmetric chiral spiro carbon is considered to be the main criteria of the bioactivities. Spirooxindole structures represent the main skeleton for various alkaloids and pharmaceutically important compounds. Among them, the naturally occurring pyrrolidinylespirooxindole alkaloid, horsifiline that exhibits anticancer activity against human brain cancer cell lines.

Objective: The objective of this study is the synthesis of novel bis spiro-cyclic 2-oxindole of pyrimido[4,5-b]quinoline derivatives and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer.

Method: An efficient one pot synthesis of bis spiro-cyclic 2-oxindole derivatives of pyrimido[4,5- b]quinoline-4,6-dione using 6-aminouracil, bis-isatin and dimedone has been developed. The cytotoxic effect against different human cell lines MCF7, HCT116 and A549 cell lines was evaluated. The derivative 6a, was found the most encouraging compound in this series and it was selected for molecular studies against MCF7.

Results: Our data indicated that compound 6a is an attractive target for breast cancer, as it inhibits proliferation, cell cycle progression and induces apoptosis of tumor cells. This inhibition is mediated by fragmentation of genomic DNA, up-regulation of [caspase-3, tumor suppressor gene p53, and pro-apoptotic gene BAX], and down-regulation of anti-apoptotic BCL2 gene. In additions it caused cell cycle arrest in S phase. This work provides an evidence of the potent effect of the new compound 6a and assists in the progress of new healing agents for cancer.

Conclusion: We have developed an efficient method for the synthesis of novel bioactive bis spirocyclic 2-oxindole derivatives incorporating pyrimido[4,5-b]quinoline derivatives. Most of our new derivatives give potent cytotoxic effect more than the standard drug Fluorouracil (5-FU) especially, compound 6a which was the most active and promising one in this series against MCF7, HCT116, and A549 cell lines.

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Neoisoliquiritigenin Inhibits Tumor Progression by Targeting GRP78-β- catenin Signaling in Breast Cancer

Background: Breast cancer mortality has been stable or decreasing in the world, its incidence and recurrence rates have sharply risen worldwide in the recent years.

Objective: To investigate the clinicopathological significance and potential function of GRP78 in the development and progression of breast cancer. To explore the effects of neoisoliquiritigenin (NISL) in breast cancer and the underlying mechanism.

Method: GRP78 was detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs), and the association between GRP78 levels and clinicopathological factors and prognosis was analyzed. The functional effects of GRP78 on breast cancer were validated by an MTT assay, foci formation assay, Matrigel invasion assay and mouse xenograft assay. The effects of NISL were tested by an MTT assay, apoptosis assay and mouse xenograft assay. A LigandFit algorithm, ATPase activity assay, western blot and IHC assay were used to discover the underlying mechanism of the effects of NSIL.

Results: GRP78 was highly expressed in breast cancer cell lines and tissues. In addition, high expression of GRP78 was correlated to poor outcomes and distant metastasis. Functional experiments showed that GRP78 promoted breast cancer proliferation and invasion in vitro and in vivo. NISL inhibited cell proliferation and induced cell apoptosis in breast cancer by directly binding to GRP78 to regulate the β-catenin pathway.

Conclusion: Taken together, these results highlighted the significance of GRP78 in breast cancer development and suggested NISL as a natural candidate to inhibit breast cancer by targeting GRP78 and β-catenin signaling.

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Vaccine options for influenza: thinking small

Bert Schepens | Dorien De Vlieger | Xavier Saelens

https://ift.tt/2qcgnh2

Ion channelopathies of the immune system

Martin Vaeth | Stefan Feske

https://ift.tt/2GJQE5C

Modulation of innate and adaptive immunity by P2X ion channels

Francesco Di Virgilio | Alba Clara Sarti | Fabio Grassi

https://ift.tt/2H7cwex

MET amplification, expression, and exon 14 mutations in colorectal adenocarcinoma

MET amplification, expression, and splice mutations at exon 14 result in dysregulation of the MET signaling pathway. The aim of this study was to identify the relationship between MET amplification, protein or mRNA expression, and mutations in colorectal cancer (CRC). MET immunohistochemistry (IHC) was used for MET protein expression analysis and fluorescence in situ hybridization (FISH) was used for MET amplification detection. Both analyses were performed in tissue microarrays (TMA) containing 294 of colorectal adenocarcinoma tissue samples and 131 samples of adjacent normal epithelial tissue.

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Lewy Body Disease: Clinical and Pathological “Overlap Syndrome” Between Synucleinopathies (Parkinson Disease) and Tauopathies (Alzheimer Disease)

Abstract

Lewy body disease (LBD) is a neurodegenerative disease resulting in dementia. It shares clinical and pathological features with Parkinson disease (PD), the most frequent synucleinopathy, Parkinson disease dementia (PDD), and Alzheimer disease (AD), a tauopathy. Even though the diagnostic criteria for these neurodegenerative diseases are clearly established, and recently revised for LBD, their precise clinical diagnosis is often difficult because LBD, PD, PDD, and AD share epidemiological, clinical, and pathological characteristics. This manuscript discusses current understanding of overlapping symptoms and the particular features of LBD, PD, and AD. It also describes features that could facilitate the diagnosis of each of these diseases. We concluded that the concept of neurodegenerative "overlap" syndrome, which includes the accepted diagnosis of LBD, may be taken in account and should contribute to clarifying LBD and definitions of close differential diagnoses. This should allow clinicians to suspect LBD at an earlier stage and provide better patient care.

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Polysome Profiling in Leishmania, Human Cells and Mouse Testis

The overall goal of polysome profiling technique is analysis of translational activity of individual mRNAs or transcriptome mRNAs during protein synthesis. The method is important for studies of protein synthesis regulation, translation activation and repression in health and multiple human diseases.

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EMCrit RACC Podcast 222 / EDECMO Podcast – Demetris Yannopoulos on ECPR-the Minneapolis Way

Yannopoulos on ECPR

EMCrit Project by Scott Weingart.

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A Fabrication and Measurement Method for a Flexible Ferroelectric Element Based on Van Der Waals Heteroepitaxy

In this paper, we present a protocol to directly grow an epitaxial yet flexible lead zirconium titanate memory element on muscovite mica.

https://ift.tt/2qg4Kop

Re-Arterialized Rat Partial Liver Transplantation with an in vivo Vessel-Oriented 70% Hepatectomy

Here, a protocol involving re-arterialized rat partial liver transplantation is presented. Specifically, 70% liver was resected in vivo by using an updated technique of vessel-oriented hepatectomy. The hepatic artery was reconstructed in an end-to-side manner. The cuff technique was modified to shorten the anastomosis time of the infrahepatic vena cava.

https://ift.tt/2qewUkt

Presurgical pazopanib for renal cell carcinoma with inferior vena caval thrombus: a single-institution study

The aim of this study was to investigate the clinical benefit of presurgical therapy with pazopanib in renal cell carcinoma (RCC) patients with a tumor thrombus extending to a high level in the vena cava. A retrospective review was performed for seven consecutive patients with RCC and tumor thrombus involving the vena cava above the hepatic vein (level 3–4, Mayo Clinic classification) treated with pazopanib without initial cytoreductive nephrectomy at our institution. The effect of pazopanib was assessed in terms of the primary site response, thrombus diameter, and height (before and after treatment) on computed tomography or MRI. The tumor thrombus level before the induction of pazopanib was 3 in one patient and 4 in the remaining six patients. After pazopanib, shrinkage of the primary site and thrombus diameter and length were observed in all patients except one (with a rhabdoid tumor). The mean decreases of primary tumor diameter, tumor thrombus diameter, and length were 14, 9, and 31 mm, respectively. The tumor thrombus level decreased in three (43%) patients and remained stable in the remaining patient. Our findings suggest that presurgical treatment with pazopanib may shrink the tumor thrombus and decrease the surgical invasiveness in RCC patients with a high-level tumor thrombus. Correspondence to Tomoaki Terakawa, PhD, MD, Department of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Chuoku, Kobe 650-0017, Hyogo Prefecture, Japan Tel: +81 78 382 6155; fax: +81 78 382 6169; e-mail: daatera0804@hotmail.com Received October 17, 2017 Accepted March 14, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Candidate Genes as Biomarkers in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome Based on mRNA Expression Profile by Next-Generation RNA-Seq Analysis

Up until now, the regulation mechanism at the level of gene during lipopolysaccharide- (LPS-) induced acute respiratory distress syndrome (ARDS) remains unclear. The discovery of differentially expressed genes (DEGs) between LPS-induced ARDS rats and normal rats by next-generation RNA sequencing analysis is of particular interest for the current study. These DEGs may help clinical diagnosis of ARDS and facilitate the selection of the optimal treatment strategy. Randomly, 20 rats were equally divided into 2 groups, the control group and the LPS group. Three rats from each group were selected at random for RNA sequencing analysis. Sequence reads were obtained from Illumina HiSeq4000 and mapped onto the rat reference genome RN6 using Hisat2. We identified 5244 DEGs (Fold_Change > 1.5, and ) in the lung tissues from LPS-treated rats compared with normal rats, including 1413 upregulated and 3831 downregulated expressed genes. Lots of chemokine family members were among the most upregulated genes in LPS group. Gene ontology (GO) analysis revealed that almost all of the most enriched and meaningful biological process terms were mainly involved in the functions like immune-inflammation response and the pathways like cytokine-cytokine receptor interaction. We also found that, as for GO molecular function terms, the enriched terms were mainly related to chemokines and cytokines. DEGs with fold change over 100 were verified by quantitative real-time polymerase chain reaction and reanalyzed by gene-gene coexpression network, and the results elucidated central roles of chemokines in LPS-induced ARDS. Our results revealed some new biomarkers for uncovering mechanisms and processes of ARDS.

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Significant Changes in Plasma Alpha-Synuclein and Beta-Synuclein Levels in Male Children with Autism Spectrum Disorder

Alpha-synuclein (α-synuclein) and beta-synuclein (β-synuclein) are presynaptic proteins playing important roles in neuronal plasticity and synaptic vesicle regulation. To evaluate the association of these two proteins and autism spectrum disorder (ASD), we investigated the plasma α-synuclein and β-synuclein levels in 39 male children with ASD (2 subgroups: 25 autism and 14 pervasive developmental disorder-not otherwise specified (PDD-NOS)) comparing with 29 sex- and age-matched controls by using enzyme-linked immunosorbent assay (ELISA). We first determined the levels of these two proteins in the ASD subgroups and found that there were no significant differences in both plasma α-synuclein and β-synuclein levels in the autism and PDD-NOS groups. Thus, we could combine the 2 subgroups into one ASD group. Interestingly, the mean plasma α-synuclein level was significantly lower () in the ASD children ( ng/mL) than in the controls ( ng/mL), while the mean plasma β-synuclein level in the ASD children ( ng/mL) was significantly higher () than in the controls ( ng/mL). This is the first study examining the associations between α-synuclein and β-synuclein and male ASD patients. We found that alterations in the plasma α-synuclein and β-synuclein levels might be implicated in the association between synaptic abnormalities and ASD pathogenesis.

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Immunomodulatory Effects of Kuseonwangdogo-Based Mixed Herbal Formula Extracts on a Cyclophosphamide-Induced Immunosuppression Mouse Model

Aim. Kuseonwangdogo is a traditional Korean immunomodulatory polyherbal prescription. However, there are no systemic findings on its complex immunomodulatory effects on in vivo models. In this study, we observed the immunomodulatory effects of Kuseonwangdogo-based mixed herbal formula aqueous extracts (MHFe) on cyclophosphamide- (CPA-) induced immunosuppression mouse model. Methods. In total, 60 male 6-week-old ICR mice (10 mice/group) were selected based on body weight 24 h after the second CPA treatment and used in this experiment. Twelve hours after the end of the last (fourth) oral administration of MHFe, the animals were sacrificed. Results. Following CPA treatment, a noticeable decrease in the body, thymus, spleen, and submandibular lymph node (LN) weights; white blood cell, red blood cell, platelet number, hemoglobin, and hematocrit concentrations; serum interferon-γ levels; splenic tumor necrosis factor-α, interleukin- (IL-) 1β, and IL-10 content; and peritoneal and splenic natural killer cell activities was observed. Depletion of lymphoid cells in the thymic cortex, splenic white pulp, and submandibular LN-related atrophic changes were also observed. However, these CPA-induced myelosuppressive signs were markedly and dose-dependently inhibited by the oral administration of 125, 250, and 500 mg/kg MHFe. Conclusion. MHFe can be a promising, potent immunomodulatory therapeutic agent for various immune disorders.

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Genotypic Characterization of Rickettsia bellii Reveals Distinct Lineages in the United States and South America

The bacterium Rickettsia bellii belongs to a basal group of rickettsiae that diverged prior to the pathogenic spotted fever group and typhus group Rickettsia species. Despite a diverse representation of R. bellii across more than 25 species of hard and soft ticks in the American continent, phylogeographical relationships among strains of this basal group-Rickettsia species are unknown; the work described here explores these relationships. DNA was extracted from 30 R. bellii tick isolates: 15 from the United States, 14 from Brazil, and 1 from Argentina. A total of 2,269 aligned nucleotide sites of 3 protein coding genes (gltA, atpA, and coxA) and 2 intergenic regions (rpmE-tRN and RC1027-xthA2) were concatenated and subjected to phylogenetic analysis by Bayesian methods. Results showed a separation of almost all isolates between North and South Americas, suggesting that they have radiated within their respective continents. Phylogenetic positions of the 30 isolates could be a result of not only their geographical origin but also the tick hosts they have coevolved with. Whether R. bellii originated with ticks in North or South America remains obscure, as our analyses did not show evidence for greater genetic divergence of R. bellii in either continent.

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Mediolateral Differences of Proteoglycans Distribution at the ACL Tibial Footprint: Experimental Study of 16 Cadaveric Knees

This study aimed to identify the staining pattern of ACL attachment blended with cartilage of the medial tibial plateau at the tibial insertion and histologically characterize the tibial footprint. Sixteen fresh frozen cadaveric knees (mean age: years) were used for this study. The specimens were bisected in the coronal plane, in accordance with the fiber orientation of the ACL tibial attachment. Adjacent sections were then stained with hematoxylin and eosin (H&E) to observe the morphology of the ACL insertion and with fast green and Safranin-O protocols to evaluate for collagen and proteoglycans (PG). The insertion area on the tibial footprint was divided into five zones in the medial to lateral direction, which was determined by division of the section from most prominent medial tibial spine to most lateral margin of ACL attachment. Then rectangular area with a vertical length that is twice the width of respective five zones was set. Stained areas of all images were quantified positively by using ImageJ software, and the value for staining area measured was defined in percentage by multiplying whole image area by 100. The mean proportion of Safranin-O staining is significantly greater nearer to the medial tibial spine (59% in zone 1, 32% in zone 2, 13% in zone 3, 13% in zone 4, and 4% in zone 5, ). The medial section of the tibial insertion area grew in size and increased in PG staining with more densely organized collagen arrangement with more fibrocartilage cells. The ACL tibial insertion showed a medially eccentric staining pattern by histological evaluation of the ACL attachment to cartilage. Our histological results of the eccentric biomaterial property in the medial tibial spine of ACL insertion area can be considered in making a more functional anatomic tibial tunnel placement.

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Impact of ICU Structure and Processes of Care on Outcomes After Severe Traumatic Brain Injury: A Multicenter Cohort Study

Objectives: It is uncertain whether dedicated neurocritical care units are associated with improved outcomes for critically ill neurologically injured patients in the era of collaborative protocol-driven care. We examined the association between dedicated neurocritical care units and mortality and the effects of standardized management protocols for severe traumatic brain injury. Design: We surveyed trauma medical directors from centers participating in the American College of Surgeons Trauma Quality Improvement Program to obtain information about ICU structure and processes of care. Survey data were then linked to the Trauma Quality Improvement Program registry, and random-intercept hierarchical multivariable modeling was used to evaluate the association between dedicated neurocritical care units, the presence of standardized management protocols and mortality. Setting: Trauma centers in North America participating in Trauma Quality Improvement Program. Patients: Data were analyzed from 9,773 adult patients with isolated severe traumatic brain injury admitted to 134 Trauma Quality Improvement Program centers between 2011 and 2013. Interventions: None. Measurements and Main Results: Only 50 ICUs (37%) were dedicated neurocritical care units, whereas 84 (63%) were general ICUs. Rates of standardized management protocols were similar comparing dedicated neurocritical care units and general ICUs. Among severe TBI patients admitted to trauma centers enrolled in Trauma Quality Improvement Program, care in a dedicated neurocritical care unit did not improve risk-adjusted in-hospital survival (odds ratio, 0.97; 95% CI, 0.80–1.19; p = 0.79). However, the presence of a standardized management protocol for these patients was associated with lower risk-adjusted in-hospital mortality (odds ratio, 0.77; 95% CI, 0.63–0.93; p = 0.009). Conclusions: Compared with dedicated neurocritical care models, standardized management protocols for severe traumatic brain injured patients are process-targeted intervention strategies that may improve clinical outcomes. The opinions, results, and conclusions reported in this article are those of the authors and are independent of funding sources. Dr. McCredie contributed to the literature search, study design, data analysis, data interpretation, writing, and critical revision. Drs. Alali, Scales, Rubenfeld, and Cuthbertson contributed to the study design, data interpretation, and critical revision. Dr. Nathens contributed to the study design, data analysis, data interpretation, and critical revision. Supplemental digital content is available for this article. Direct URL ­citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported, in part, by a de Souza Chair in Trauma Research. Dr. Nathens received other support from a de Souza Chair in Trauma Research. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Victoria.McCredie@uhn.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Early Enteral Nutrition Provided Within 24 Hours of ICU Admission: A Meta-Analysis of Randomized Controlled Trials

Objectives: To identify, appraise, and synthesize the most current evidence to determine whether early enteral nutrition alters patient outcomes from critical illness. Data Sources: Medline and Embase were searched. The close out date was November 20, 2017. Study Selection: Early enteral nutrition was defined as a standard formula commenced within 24 hours of ICU admission. Comparators included any form of nutrition support "except" early enteral nutrition. Only randomized controlled trials conducted in adult patients requiring treatment in an ICU were eligible for inclusion. Data Extraction: The primary outcome was mortality. Secondary outcomes included pneumonia, duration of mechanical ventilation, and ICU and hospital stay. Data Synthesis: Six-hundred ninety-nine full-text articles were retrieved and screened. Sixteen randomized controlled trials enrolling 3,225 critically ill participants were included. Compared with all other types of nutrition support, commencing enteral nutrition within 24 hours of ICU admission did not result in a reduction in mortality (odds ratio, 1.01; 95% CI, 0.86–1.18; p = 0.91; I2 = 32%). However, there was a differential treatment effect between a priori identified subgroups (p = 0.032): early enteral nutrition reduced mortality compared with delayed enteral intake (odds ratio, 0.45; 95% CI, 0.21–0.95; p = 0.038; I2 = 0%), whereas a mortality difference was not detected between early enteral nutrition and parenteral nutrition (odds ratio, 1.04; 95% CI, 0.89–1.22; p = 0.58; I2 = 30%). Overall, patients who were randomized to receive early enteral nutrition were less likely to develop pneumonia (odds ratio, 0.75; 95% CI, 0.60–0.94; p = 0.012; I2 = 48%). Conclusions: Overall, there was no difference between early enteral nutrition and all other forms of nutrition support. A priori planned subgroup analysis revealed early enteral nutrition reduced mortality and pneumonia compared with delayed enteral intake; however, there were no clear clinical advantages of early enteral nutrition over parenteral nutrition. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Dr. Tian's Visiting Fellowship with the University of Sydney's Northern Clinical School Intensive Care Research Unit was enabled by a grant from the Special Science and Technology Research Funds for Public Welfare Projects (201502022) from National Health and Family Planning Commission of China. Dr Allingstrup reported receiving academic research grants from Fresenius Kabi Deutschland GmbH, Medinor A/S Denmark and COSMED Irl, Rome, Italy, and speakers honoraria from Fresenius Kabi A/S Denmark, Baxter Healthcare A/S Denmark and Nutricia A/S Denmark. Dr. Doig's institution received funding from research grants (not for the current project) from Baxter Healthcare Pty Ltd and Fresenius Kabi Deutschland GmbH, and he received funding (speakers honoraria) from Fresenius Kabi Deutschland GmbH, Baxter Healthcare Australia, Pty, Nestle Healthcare, Vevy, Switzerland, and Nutricia Pharmaceutical (Wuxi) Co, China. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: gdoig@med.usyd.edu.au Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Ventilator Bundle and Its Effects on Mortality Among ICU Patients: A Meta-Analysis

Objectives: To assess the effectiveness of the ventilator bundle in the reduction of mortality in ICU patients. Data Sources: PubMed, Scopus, Web of Science, Cochrane Library for studies published until June 2017. Study Selection: Included studies: randomized controlled trials or any kind of nonrandomized intervention studies, made reference to a ventilator bundle approach, assessed mortality in ICU-ventilated adult patients. Data Extraction: Items extracted: study characteristics, description of the bundle approach, number of patients in the comparison groups, hospital/ICU mortality, ventilator-associated pneumonia–related mortality, assessment of compliance to ventilator bundle and its score. Data Synthesis: Thirteen articles were included. The implementation of a ventilator bundle significantly reduced mortality (odds ratio, 0.90; 95% CI, 0.84–0.97), with a stronger effect with a restriction to studies that reported mortality in ventilator-associated pneumonia patients (odds ratio, 0.71; 95% CI, 0.52–0.97), to studies that provided active educational activities was analyzed (odds ratio, 0.88; 95% CI, 0.78–0.99), and when the role of care procedures within the bundle (odds ratio, 0.87; 95% CI, 0.77–0.99). No survival benefit was associated with compliance to ventilator bundles. However, these results may have been confounded by the differential implementation of evidence-based procedures at baseline, which showed improved survival in the study subgroup that did not report implementation of these procedures at baseline (odds ratio, 0.82; 95% CI, 0.70–0.96). Conclusions: Simple interventions in common clinical practice applied in a coordinated way as a part of a bundle care are effective in reducing mortality in ventilated ICU patients. More prospective controlled studies are needed to define the effect of ventilator bundles on survival outcomes. Drs. Pileggi and Pavia conceived and designed the study. Drs. Pileggi, Mascaro, and Nobile did the literature review and data collection. Drs. Mascaro and Bianco did the statistical analysis. Drs. Pileggi and Pavia wrote the article. All authors contributed to the interpretation of the data and writing of the article and agree with its content and conclusions. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: pavia@unicz.it Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Inclusion of Unstructured Clinical Text Improves Early Prediction of Death or Prolonged ICU Stay

Objectives: Early prediction of undesired outcomes among newly hospitalized patients could improve patient triage and prompt conversations about patients' goals of care. We evaluated the performance of logistic regression, gradient boosting machine, random forest, and elastic net regression models, with and without unstructured clinical text data, to predict a binary composite outcome of in-hospital death or ICU length of stay greater than or equal to 7 days using data from the first 48 hours of hospitalization. Design: Retrospective cohort study with split sampling for model training and testing. Setting: A single urban academic hospital. Patients: All hospitalized patients who required ICU care at the Beth Israel Deaconess Medical Center in Boston, MA, from 2001 to 2012. Interventions: None. Measurements and Main Results: Among eligible 25,947 hospital admissions, we observed 5,504 (21.2%) in which patients died or had ICU length of stay greater than or equal to 7 days. The gradient boosting machine model had the highest discrimination without (area under the receiver operating characteristic curve, 0.83; 95% CI, 0.81–0.84) and with (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.88–0.90) text-derived variables. Both gradient boosting machines and random forests outperformed logistic regression without text data (p

https://ift.tt/2HgREza

Markedly Deranged Injury Site Metabolism and Impaired Functional Recovery in Acute Spinal Cord Injury Patients With Fever

Objectives: To characterize the effect of fever after acute, traumatic spinal cord injury on injury site metabolism and patient outcome. Design: Longitudinal cohort study. In 44 patients (London cohort), we determined the effect of fever on intrathecal injury site metabolism by analyzing 1,767 hours of intraspinal pressure and 759 hours of microdialysis data. We also determined the effect of fever burden, computed for the first 2 weeks in hospital, on neurologic outcome. A distinct cohort of 33 patients (Berlin cohort) was used to independently validate the effect of fever burden on outcome. Setting: ICUs in London and Berlin. Patients: Seventy-seven patients with acute, traumatic spinal cord injuries. Interventions: In the London patients, a pressure probe and a microdialysis catheter were placed intradurally on the surface of the injured cord for up to a week. Measurements and Main Results: Fever (> 37.5°C) occurs frequently (37% of the time) after spinal cord injury. High-grade fever (≥ 38°C) was associated with significantly more deranged metabolite levels than normothermia (36.5–37.5°C), that is, lower tissue glucose (median 2.0 vs 3.3 mM), higher lactate (7.8 vs 5.4 mM), higher glutamate (7.8 vs 6.4 µM), and higher lactate-to-pyruvate ratio (38.9 vs 29.3). High-grade fever was particularly detrimental on injury site metabolism when the peripheral leukocyte count was high. In the London and Berlin cohorts, high fever burden correlated with less neurologic improvement. Conclusions: Early after spinal cord injury, fever is associated with more deranged injury site metabolism than normothermia and worse prognosis. London patients were monitored and followed up at St. George's Hospital, London, United Kingdom. Analysis of Berlin patient data was done at Trauma Hospital, Berlin, Germany. Drs. Papadopoulos and Saadoun are cosenior authors. Supported, in part, by Wings for Life Spinal Cord Research Foundation (to Drs. Papadopoulos and Saadoun), Fletcher Fund (to Dr. Papadopoulos), Neurosciences Research Foundation (to Drs. Gallagher and Papadopoulos), and London Deanery (to Dr. Gallagher). Drs. Gallagher's and Papadopoulos's institutions received funding from the Wings for Life spinal cord research foundation and the Neurosciences Research Foundation. Dr. Schwab is an OSU Discovery Theme Scholar and received support by the Era-Net-NEURON Program of the European Union (SILENCE Grant #01EW170A), NIDILRR (Grant #90SI5020), and the W.E. Hunt & C.M. Curtis Endowment. Dr. Kopp received funding from the Italian Ministry of Health (reviewer). Dr. Saadoun's institution received funding from research grants. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: ssaadoun@sgul.ac.uk Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Early Evidence of Sepsis-Associated Hyperperfusion—A Study of Cerebral Blood Flow Measured With MRI Arterial Spin Labeling in Critically Ill Septic Patients and Control Subjects

Objectives: Mechanisms underlying sepsis-associated encephalopathy remain unclear, but reduced cerebral blood flow, alone or in conjunction with altered autoregulation, is reported as a potential contributor. We compared cerebral blood flow of control subjects and vasopressor-dependent septic patients. Design: Randomized crossover study. Setting: MRI with arterial spin labeling. Patients: Ten sedated septic patients on mechanical ventilation (four with controlled chronic hypertension) and 12 control subjects (six with controlled chronic hypertension) were enrolled. Mean ± SD ages were 61.4 ± 10.2 and 44.2 ± 12.8 years, respectively (p = 0.003). Mean Acute Physiology and Chronic Health Evaluation II score of septic patients at ICU admission was 27.7 ± 6.6. Interventions: To assess the potential confounding effects of sedation and mean arterial pressure, we measured cerebral blood flow with and without sedation with propofol in control subjects and at a target mean arterial pressure of 65 mm Hg and greater than or equal to 75 mm Hg in septic patients. The sequence of sedation versus no sedation and mean arterial pressure targets were randomized. Measurements and Main Results: In septic patients, cerebral blood flow measured at a mean arterial pressure target of 65 mm Hg (40.4 ± 10.9 mL/100 g/min) was not different from cerebral blood flow measured at a mean arterial pressure target of greater than or equal to 75 mm Hg (41.3 ± 9.8 mL/100 g/min; p = 0.65). In control subjects, we observed no difference in cerebral blood flow measured without and with sedation (24.8 ± 4.2 vs 24.9 ± 5.9 mL/100 g/min; p = 0.93). We found no interaction between chronic hypertension and the effect of sedation or mean arterial pressure targets. Cerebral blood flow measured in sedated septic patients (mean arterial pressure target 65 mm Hg) was 62% higher than in sedated control subjects (p = 0.001). Conclusions: In septic patients, cerebral blood flow was higher than in sedated control subjects and did not vary with mean arterial pressure targets. Further research is required to understand the clinical significance of cerebral hyperperfusion in septic patients on vasopressors and to reassess the neurologic effects of current mean arterial pressure targets in sepsis. This work was performed at Centre de recherche du CHUS, Sherbrooke, QC, Canada. Dr. F. Lamontagne conceived the study. Ms. Masse, Ms. Richard, and Drs. D'Aragon, Palanchuck, Lepage, and F. Lamontagne initiated the study design. Drs. St-Arnaud, Mayette, Adhikari, Fraser, Carpentier, Gauthier, Lanthier, Touchette, A. Lamontagne, Chénard, Mehta, Sansoucy, and Croteau helped with implementation. Drs. D'Aragon, Fraser, Carpentier, Sansoucy, Lepage, and F. Lamontagne are grant holders. Drs. Adhikari and F. Lamontagne provided statistical expertise in clinical trial design. All authors contributed to refinement of the study protocol and approved the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported, in part, by grant from the Centre de Recherche du CHUS. Drs. D'Aragon, Fraser, Carpentier, Palanchuck, Gauthier, Croteau, Lepage, and F. Lamontagne members of the Fonds de recherche du Québec-Santé funded CRCHUS. Dr. Mayette received support for article research from local funding. Dr. Carpentier's institution received funding for consulting from UniQure Biopharma, Siemens Healthcare/Molecular Imaging, and Janssen; for research grants from Merck Sharpe and Dome (UdeS), GlaxoSmithKline (chair), Janssen, UniQure Biopharma, Caprion (Canadian Institutes Health Research University of Toronto), and Jonhson & Jonhson; for invited speaker fees from Siemens Healthcare/Molecular Imaging, Merck, Amgen, UniQure, and Medtronic; for sponsored research from Hamilton Health Research, Novartis, AstraZeneca, BMS, Sanofi Aventis, Merck, Pfizer, NovoNordisk, The Medicine Companies, Exelixis, Amgen, and UniQure Biopharma; and for sponsorship for scientific events from Siemens, Amgen, Merck, Takeda, Pfizer, Agilent, Janssen, NovoNordisk, Boehringer Lilly, AstraZeneca, Sanofi, Amgen, Aegerion, and Financière Sun Life. Dr. Lepage received support for article research from pilot institutional funding. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Francois.Lamontagne@USherbrooke.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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End-of-Life Care in ICUs in East Asia: A Comparison Among China, Korea, and Japan

Objectives: To compare physicians' perceptions and practice of end-of-life care in the ICU in three East Asian countries cultures similarly rooted in Confucianism. Design: A structured and scenario-based survey of physicians who managed ICU patients from May 2012 to December 2012. Setting: ICUs in China, Korea, and Japan. Subjects: Specialists who are either intensivists or nonintensivist primary attending physicians in charge of patients (195 in China, 186 in Korea, 224 in Japan). Interventions: None. Measurements and Main Results: Country was independently associated with differences in the practice of limiting multiple forms of life-sustaining treatments on multivariable generalized linear model analysis. Chinese respondents were least likely to apply do-not-resuscitate orders, even if they existed (p

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An Open-Loop, Physiologic Model–Based Decision Support System Can Provide Appropriate Ventilator Settings

Objectives: To evaluate the physiologic effects of applying advice on mechanical ventilation by an open-loop, physiologic model–based clinical decision support system. Design: Prospective, observational study. Setting: University and Regional Hospitals' ICUs. Patients: Varied adult ICU population. Interventions: Advice were applied if accepted by physicians for a period of up to 4–8 hours. Measurements and Main Results: Seventy-two patients were included for data analysis. Acceptance of advice was high with 95.7% of advice applied. In 41 patients in pressure support ventilation, following system advice led to significant decrease in PS, with PS reduced below 8 cm H2O in 15 patients (37%), a level not prohibiting extubation. Fraction of end-tidal CO2 values did not change, and increase in respiratory rate/VT was within clinical limits, indicating that in general, the system maintained appropriate patient breathing effort. In 31 patients in control mode ventilation, pressure control and tidal volume settings were decreased significantly, with tidal volume reduced below 8 mL/kg predicted body weight in nine patients (29%). Minute ventilation was maintained by a significant increase in respiratory rate. Significant reductions in FIO2 were seen on elevated baseline median values of 50% in both support and control mode–ventilated patients, causing clinically acceptable reductions in oxygen saturation. Conclusions: The results indicate that during a short period, the clinical decision support system provided appropriate suggestions of mechanical ventilation in a varied ICU population, significantly reducing ventilation to levels which might be considered safe and beneficial. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Drs. Karbing's, Dey's, and Rees' institutions received funding from Mermaid Care. Drs. Dey and Rees received support for article research from Mermaid Care. Drs. Karbing and Rees have performed consultancy work for Mermaid Care A/S. Dr. Karbing received funding from Mermaid Care. Dr. Rees received funding from Mermaid Care (board member and minor shareholder). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sr@hst.aau.dk Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Clinical Outcomes and Mortality Impact of Hyperbaric Oxygen Therapy in Patients With Carbon Monoxide Poisoning

Objectives: Carbon monoxide poisoning affects 50,000 per year in the United States alone. Mortality is approximately 3%, and up to 40% of survivors suffer from permanent neurocognitive and affective deficits. Hyperbaric oxygen therapy has shown benefit on reducing the long-term neurologic sequelae of carbon monoxide poisoning but has not demonstrated improved survival. The objective of this study is to assess the efficacy of hyperbaric oxygen for acute and long-term mortality in carbon monoxide poisoning using a large clinical databank. Design: Retrospective analysis. Setting: University of Pittsburgh Medical Center healthcare system (Pittsburgh, PA). Patients: One-thousand ninety-nine unique encounters of adult patients with carbon monoxide poisoning. Interventions: None. Measurements and Main Results: Baseline demographics, laboratory values, hospital charge transactions, discharge disposition, and clinical information from charting were obtained from the electronic medical record. In propensity-adjusted analysis, hyperbaric oxygen therapy was associated with a reduction in inpatient mortality (absolute risk reduction, 2.1% [3.7–0.9%]; p = 0.001) and a reduction in 1-year mortality (absolute risk reduction, 2.1% [3.8–0.4%]; p = 0.013). Conclusions: These data demonstrate that hyperbaric oxygen is associated with reduced acute and reduced 1-year mortality. Further studies are needed on the mortality effects of hyperbaric oxygen therapy in carbon monoxide poisoning. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Dr. Rose disclosed that he and Dr. Gladwin are shareholders in Globin Solutions and are coinventors of provisional and pending patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for carbon monoxide poisoning. Globin Solutions, Inc. has licensed this technology. Dr Rose is an officer and director of Globin Solutions, Inc. Dr Gladwin is a director and advisor of Globin Solutions, Inc. Dr. Gladwin is a coinventor on patents directed to the use of nitrite salts in cardiovascular diseases and is a coinvestigator in a research collaboration with Bayer Pharmaceuticals to evaluate riociguate as a treatment for patients with sickle cell disease. Drs. Rose and Gladwin received support for article research from the National Institutes of Health. Dr. Rose also received support for article research from the Francis Family Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: gladwinmt@upmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Septate Uterus in a Girl with Rubinstein–Taybi Syndrome

Rubinstein–Taybi syndrome is an extremely rare plurimalformative condition that can affect any organ. However, reports regarding gynecological problems are unusual. We report the first case of a septate uterus in an adolescent with this syndrome, in agreement with the American Society for Reproductive Medicine (ASRM) and the Congenital Uterine Malformations by Expert (CUME) criteria for uterine septum. Additional studies are required to determine whether there is an increased frequency of müllerian duct anomalies with the condition. Our report extends the data on the clinical phenotype associated with Rubinstein–Taybi syndrome.

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Evaluation of Cytochalasin B-Induced Membrane Vesicles Fusion Specificity with Target Cells

Extracellular vesicles (EV) represent a promising vector system for biomolecules and drug delivery due to their natural origin and participation in intercellular communication. As the quantity of EVs is limited, it was proposed to induce the release of membrane vesicles from the surface of human cells by treatment with cytochalasin B. Cytochalasin B-induced membrane vesicles (CIMVs) were successfully tested as a vector for delivery of dye, nanoparticles, and a chemotherapeutic. However, it remained unclear whether CIMVs possess fusion specificity with target cells and thus might be used for more targeted delivery of therapeutics. To answer this question, CIMVs were obtained from human prostate cancer PC3 cells. The diameter of obtained CIMVs was 962,13 ± 140,6 nm. We found that there is no statistically significant preference in PC3 CIMVs fusion with target cells of the same type. According to our observations, the greatest impact on CIMVs entry into target cells is by the heterophilic interaction of CIMV membrane receptors with the surface proteins of target cells.

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