Synthesis and Dynamic Behavior of Chiral NNO-Scorpionate Zinc Initiators for the Ring-Opening Polymerization of Cyclic Esters

Abstract

The reaction of chiral alcohol–scorpionate compounds bpzbeH [bpzbeH = 1,1-bis(3,5-dimethylpyrazol-1-yl)-3,3-dimethyl-2-butanol] or bpzteH [bpzteH = 2,2-bis(3,5-dimethylpyrazol-1-yl)-1-para-tolylethanol] with [ZnR₂] (R = Me, Et, CH₂SiMe₃) in a 1:2 molar ratio afforded the dinuclear chiral zinc alkyls [Zn(R)(κ²-NNµ-O)Zn(R)₂] (1–4) [κ²-NNµ-O = bpzbe, R = Me (1), Et (2), CH₂SiMe₃ (3); bpzte, R = Et (4)]. Subsequent alcoholysis or thioalcoholysis reaction with ArEH (1 equiv.; E = O, S; Ar = 2,6-C₆H₃Me₂) yielded the chiral dinuclear mixed alkyl–alryl oxides/thioaryl oxides [(ZnR)₂(κN:κN-µ-O)(µ-EAr)] (5–12) [κN:κN-µ-O = bpzbe, E = O, R = Me (5), Et (6), CH₂SiMe₃ (7); bpzte, E = O, R = Et (8); bpzbe, E = S, R = Me (9), Et (10), CH₂SiMe₃ (11); bpzte, E = S, R = Et (12)]. The alcoholysis reaction of the previously reported monoalkyls [Zn(Me)(κ³-NNO)] or [Zn(R)(κ-NNµ-O)]₂ with ArOH (1 equiv., Ar = 2,6-C₆H₃Me₂) afforded the chiral aryl oxides [Zn(OAr)(κ²-NNµ-O)]₂ (13–14) [κ²-NNµ-O = bpzbe (13); bpzte (14)]. The X-ray crystal structures of 3, 5, 6, and 14 confirmed a dinuclear structure in all cases with the alkoxide of the heteroscorpionates in a µ-bridging mode between the Zn^II centers. Variable-temperature NMR spectroscopic studies were carried out to study their dynamic behavior in solution. Complexes 1–9 and 12 can act as single-component initiators for the ROP of ϵ-CL and L-/rac-LA, and afforded materials with low molecular weights and narrow monomodal molecular weight distributions. MALDI-TOF mass spectra confirmed that for 5–8 the initiation occurred through nucleophilic attack by the alkoxide group, rather than the alkyl group, on the lactide monomer. Furthermore, inspection of the kinetic parameters showed propagations with a pseudo-first-order dependence on monomer and catalyst concentrations. Microstructural analysis of poly(rac-lactide) revealed that the mixed alkyl/aryl oxide-substituted initiators exert a moderate level of heteroselectivity (P_s = 0.66).

A new series of chiral dinuclear trisalkyl- and alkyl–aryl oxide-containing zinc heteroscorpionates complexes, namely, [Zn(R)(κ²-NNµ-O)Zn(R)₂] and [(ZnR)₂(κN:κN-µ-O)(µ-OAr)], respectively, has been synthesized. Their dynamic behavior has been studied. Both families act as single-component living initiators for the ring-opening polymerization of ϵ-CL and L-/rac-LA.

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Controlled Synthesis of Pnicogen–Chalcogen Polycations in Ionic Li­quids

Abstract

Three new pnicogen–chalcogen polycations were synthesized under specific conditions in the Lewis-acidic ionic liquids (ILs) [EMIm]X·nAlX₃ and [BMIm]X·nAlX₃ (X = Cl, Br; [EMIm]: 1-ethyl-3-methylimidazolium, [BMIm]: 1-butyl-3-methylimidazolium) and crystallized as their tetrahalogenidoaluminate salts. Single-crystal X-ray diffraction revealed the new polycation [Bi₆Te₄Br₂]⁴⁺ in triclinic [Bi₆Te₄Br₂](AlBr₄)₄ as the reaction product of bismuth, tellurium, and bismuth tribromide. Substitution of the elements with Bi₂Te₃ yielded the heterocubane [Bi₄Te₄]⁴⁺ in tetragonal [Bi₄Te₄](AlBr₄)₄, which crystallizes isotypically to its known chlorine counterpart. The latter is also accessible from ILs. The interactions between cations and anions were evaluated by quantum-chemical calculations. Bi₂S₃, which is insoluble in most media, readily dissolves in the employed IL and forms the new augmented heterocubane [Bi₃S₄AlCl]³⁺, which crystallizes with the complex anion [S(AlCl₃)₃]^2– as triclinic [Bi₃S₄AlCl][S(AlCl₃)₃]AlCl₄. Quantum-chemical calculations support the assignment of elements in this compound. The monoclinic crystal structure of [Sb₁₃Se₁₆](AlCl₄)₆(Al₂Cl₇) contains a new member of the small family of pnicogen–chalcogen spiro-heterocubanes.

Heteropolycations: Three new pnicogen–chalcogen polycations were synthesized in imidazolium-based Lewis-acidic ionic liquids (IL) at moderate temperatures. Bi₂S₃, usually soluble only under harsh conditions, readily dissolves and reacts in the employed IL to give a quaternary polycation. The choice of starting materials and the reaction temperature were identified as important control parameters.

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Rare-Earth Metal Oxo/Hydroxo Clusters – Synthesis, Structures, and Applications

Abstract

Multinuclear rare-earth metal coordination clusters bridged by oxo/hydroxo units have emerged from being lab curiosities to become a readily accessible class of compounds. New synthetic strategies for accessing these compounds on reasonable scales have been established. Clusters of different sizes have been investigated in terms of their magnetic and photophysical properties. Some preliminary biological applications have also been established.

The synthesis and the structures of rare-earth metal oxo/hydroxo clusters are reviewed. The clusters are very robust, which makes them ideal materials for further chemical, physical, and biological studies.

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Abnormal N-Heterocyclic-Carbene-Mediated Fixation of CO2 and N2O, and the Activation of Tetrahydro­furan and Tetrahydrothiophene under Ambient Conditions

Abstract

A strong σ-donor abnormal N-heterocyclic carbene (aNHC), 1,3-bis(2,6-diisopropylphenyl)-2,4-diphenylimidazol-5-ylidene (L1), reacted with B(C₆F₅)₃ in the presence of CO₂ and N₂O to form the adducts [aNHC·CO₂·B(C₆F₅)₃] (1) and [aNHC·N₂O·B(C₆F₅)₃] (2), respectively, in high yields at room temperature within a very short period of time. Furthermore, this aNHC/B(C₆F₅)₃ reagent system was found to be very efficient for the ring-opening of tetrahydrofuran (thf) and tetrahydrothiophene (tht), affording 3 and 4, respectively, within 5–10 min at room temperature in good yields. Interestingly, this aNHC forms the air-stable Lewis acid/base adduct [aNHC·B(C₆F₅)₃] (5) with B(C₆F₅)₃ in the absence of any suitable substrate upon keeping this mixture in solution. DFT calculations showed that the Lewis acid/base adduct 5 is energetically less stable than compounds 1–4, and this may be the driving force for the formation of compounds 1–4 in the presence of small molecules such as CO₂, N₂O, thf and tht. All the new compounds were characterized spectroscopically (¹H, ¹³C, ¹⁹F and ¹¹B NMR, IR spectroscopy) in solution and the solid-state structures were unambiguously established by single-crystal X-ray diffraction analysis.

The abnormal N-heterocyclic carbene, 1,3-bis(2,6-diisopropylphenyl)-2,4-diphenylimidazole-5-ylidene, reacts with B(C₆F₅)₃ in the presence of CO₂ or N₂O to form [aNHC·CO₂·B(C₆F₅)₃] or [aNHC·N₂O·B(C₆F₅)₃], respectively, in high yields at room temperature within a very short period of time.

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Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional co-receptors

Abstract

Background

Neuropilin-1 (NRP-1) is a transmembrane glycoprotein participating in the growth and metastasis of cancer cells as multifunctional co-receptors by interacting with the signaling pathways. However, its role in gastric cancer has not yet been clarified. This study aims to investigate whether NRP-1 expression is associated with the clinicopathology of gastric cancer, and involved in the growth and metastasis of gastric cancer cells.

Methods

NRP-1 expression in clinical gastric cancer specimens was examined by immunohistochemistry and its association with clinicopathology analyzed. The expression of NRP-1 in a panel of human gastric cancer cells was examined by real-time RT-PCR and immunoblotting. Stable transfectants depleted of NRP-1, termed MGC-803-NRP^low, were generated from MGC-803 cells. Cell proliferation was analyzed by the Cell Counting Kit-8 and Bromodeoxyuridine incorporation assays, and migrating ability analyzed by migration assays. The xenograft model was used to assess the effects of NRP-1 depletion on tumorigenesis, growth, metastasis and therapeutic potentials. The role of NRP-1 as co-receptors in the signaling pathways stimulated by ligands was examined. The key molecules involved in cell proliferation, migration and related signaling pathways were detected by immunoblotting.

Results

Gastric cancer tissues expressed higher levels of NRP-1 compared to normal gastric mucosa. Its expression correlated with clinical staging, tumor differentiation and pathological types. NRP-1 depletion inhibited cell proliferation by inducing cell cycle arrest in the G1/S phase by upregulating p27, and downregulating cyclin E and cyclin-dependent kinase 2. NRP-1 depletion reduced the ability of cells to migrate by inhibiting the phosphorylation of focal adhesion kinase. NRP-1 depletion suppressed tumorigenesis, tumor growth and lung metastasis by inhibiting cell proliferation and tumor angiogenesis in situ. Therapeutic NRP-1 shRNA inhibited the growth of established BGC823 tumors. Depletion of NRP-1 inhibited the activation of VEGF/VEGFR2, EGF/EGFR and HGF/c-Met pathways stimulated by respective recombinant human VEGF-165, EGF and HGF proteins.

Conclusions

The present results indicate that NRP-1 may be a potentially valuable biomarker and therapeutic target for gastric cancer.

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Eliciting cytotoxic T lymphocytes against human laryngeal cancer-derived antigens: evaluation of dendritic cells pulsed with a heat-treated tumor lysate and other antigen-loading strategies for dendritic-cell-based vaccination

Abstract

Background

Dendritic cells (DCs) have been used successfully in clinical pilot studies. However, tumor-specific immunity and clinical responses were only induced in certain cancer patients. It has been well documented that immunotherapy efficacy can be optimized for responses using antigen pulsing.

Methods

The human laryngeal squamous cell cancer (LSCC) cell line SNU899 was used to evaluate the in vitro anti-tumor efficacy of three different preparations of dendritic cell (DC) vaccines consisting of either whole tumor cells or their derivatives including: i) DCs pulsed with a tumor cell supernatant (DC-TCS), ii) DCs pulsed with whole-cell tumor stressed lysate (DC-TSL), and iii) DCs pulsed with irradiated tumor cells (DC-ITC).

Results

Our results showed that DC-TSL is an effective source of tumor-associated antigens (TAAs) for pulsing DCs. DC-TSL induced the highest expansion of TAA-specific T cells, the strongest Th1 cytokine response, and the most potent cytotoxic T lymphocyte (CTL) activity. DC-TCS and DC-ITC inhibited T cell activation but induced a certain extent of CTL activity.

Conclusions

These data suggest that DC-TSL is a more potent inducer of antitumor immunity against laryngeal cancer than other antigen-loading strategies using whole tumor cell materials. This strategy provides an alternative approach for DC-based immunotherapy for laryngeal cancer.

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Integrated analysis of microRNA regulatory network in nasopharyngeal carcinoma with deep sequencing

Abstract

Background

MicroRNAs (miRNAs) have been shown to play a critical role in the development and progression of nasopharyngeal carcinoma (NPC). Although accumulating studies have been performed on the molecular mechanisms of NPC, the miRNA regulatory networks in cancer progression remain largely unknown. Laser capture microdissection (LCM) and deep sequencing are powerful tools that can help us to detect the integrated view of miRNA-target network.

Methods

Illumina Hiseq2000 deep sequencing was used to screen differentially expressed miRNAs in laser-microdessected biopsies between 12 NPC and 8 chronic nasopharyngitis patients. The result was validated by real-time PCR on 201 NPC and 25 chronic nasopharyngitis patients. The potential candidate target genes of the miRNAs were predicted using published target prediction softwares (RNAhybrid, TargetScan, Miranda, PITA), and the overlay part was analyzed in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological process. The miRNA regulatory network analysis was performed using the Ingenuity Pathway Analysis (IPA) software.

Results

Eight differentially expressed miRNAs were identified between NPC and chronic nasopharyngitis patients by deep sequencing. Further qRT-PCR assays confirmed 3 down-regulated miRNAs (miR-34c-5p, miR-375 and miR-449c-5p), 4 up-regulated miRNAs (miR-205-5p, miR-92a-3p, miR-193b-3p and miR-27a-5p). Additionally, the low level of miR-34c-5p (miR-34c) was significantly correlated with advanced TNM stage. GO and KEGG enrichment analyses showed that 914 target genes were involved in cell cycle, cytokine secretion and tumor immunology, and so on. IPA revealed that cancer was the top disease associated with those dysregulated miRNAs, and the genes regulated by miR-34c were in the center of miRNA-mRNA regulatory network, including TP53, CCND1, CDK6, MET and BCL2, and the PI3K/AKT/ mTOR signaling was regarded as a significant function pathway in this network.

Conclusion

Our study presents the current knowledge of miRNA regulatory network in NPC with combination of bioinformatics analysis and literature research. The hypothesis of miR-34c regulatory pathway may be beneficial in guiding further studies on the molecular mechanism of NPC tumorigenesis.

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Safe and efficient method for cryopreservation of human induced pluripotent stem cell-derived neural stem and progenitor cells by a programmed freezer with a magnetic field

Publication date: Available online 22 January 2016
Source:Neuroscience Research
Author(s): Yuichiro Nishiyama, Akio Iwanami, Jun Kohyama, Go Itakura, Soya Kawabata, Keiko Sugai, Soraya Nishimura, Rei Kashiwagi, Kaori Yasutake, Miho Isoda, Morio Matsumoto, Masaya Nakamura, Hideyuki Okano
Stem cells represent a potential cellular resource in the development of regenerative medicine approaches to the treatment of pathologies in which specific cells are degenerated or damaged by genetic abnormality, disease, or injury. Securing sufficient supplies of cells suited to the demands of cell transplantation, however, remains challenging, and the establishment of safe and efficient cell banking procedures is an important goal. Cryopreservation allows the storage of stem cells for prolonged time periods while maintaining them in adequate condition for use in clinical settings. Conventional cryopreservation systems include slow-freezing and vitrification both have advantages and disadvantages in terms of cell viability and/or scalability. In the present study, we developed an advanced slow-freezing technique using a programmed freezer with a magnetic field called Cells Alive System (CAS) and examined its effectiveness on human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs). This system significantly increased cell viability after thawing and had less impact on cellular proliferation and differentiation. We further found that frozen-thawed hiPSC-NS/PCs were comparable with non-frozen ones at the transcriptome level. Given these findings, we suggest that the CAS is useful for hiPSC-NS/PCs banking for clinical uses involving neural disorders and may open new avenues for future regenerative medicine.



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Improved Quantification of Arterial Spin Labelling Images using Partial Volume Correction Techniques

Oliver, RA; (2015) Improved Quantification of Arterial Spin Labelling Images using Partial Volume Correction Techniques. Doctoral thesis, UCL (University College London). Green open access

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Infrared spectroscopy as a clinical diagnostic method for detection of disease states: developments and applications in kidney diseases and cancer diagnoses

Oliver, KV; (2015) Infrared spectroscopy as a clinical diagnostic method for detection of disease states: developments and applications in kidney diseases and cancer diagnoses. Doctoral thesis, UCL (University College London). Green open access

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High-Resolution and High-Throughput Plasmonic Photopatterning of Complex Molecular Orientations in Liquid Crystals

A plasmonic photopatterning technique is proposed and demonstrated for aligning the molecular orientation in liquid crystals (LCs) in patterns with designer complexity. Using plasmonic metamasks in which target molecular directors are encoded, LC alignments of arbitrary planar patterns can be achieved in a repeatable and scalable fashion withunprecedentedly high spatial resolution and high throughput.

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Variable severity of cardiovascular phenotypes in patients with an early-onset form of Marfan syndrome harboring FBN1 mutations in exons 24–32

Abstract

A subgroup of patients with Marfan syndrome (MFS) who have mutations in exons 24–32 of the FBN1 gene manifests severe atrioventricular valve insufficiency and skeletal problems as early as the neonatal period. These patients usually die in the first 2 years of life, thus a region between exons 24 and 32 of FBN1 is recognized as a critical region for this neonatal form of MFS (nMFS). Here, we report five consecutive patients who manifested a cardiovascular phenotype until infancy with mutations in the critical region for nMFS. Although three of these patients showed severe mitral regurgitation and died before reaching 1 year of age, the remaining two patients survived for over 5 years under medical and/or surgical interventions. Two splicing mutations and one missense mutation were identified in the three deceased patients, whereas two missense mutations were found in the two survivors. Currently, the clinical severity of patients with early-onset MFS harboring mutations in the critical region for nMFS seem to be more variable than ever thought, and intensive treatments are recommended even in this subgroup of patients with MFS.

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A case of IgG4-related lymphadenopathy, pericarditis, coronary artery periarteritis and luminal stenosis

Abstract

Immunoglobulin G4 (IgG4)-related disease is an emerging new clinicopathological disorder that is characterized by elevation of serum IgG4 levels and histological findings of IgG4-positive plasmacytic infiltration. IgG4-related disease may appear synchronously or metachronously in a wide variety of organs. The current patient was found to have pericardial effusion and retroperitoneal fibrosis. He was subsequently diagnosed with coronary artery stenosis. ¹⁸F-FDG positron emission tomography showed enhanced FDG uptake in lymph nodes as well as pericardial and peri-aortic tissue. Histopathology of the mediastinal lymph node showed the infiltration of numerous IgG4-positive cells, leading to the diagnosis of IgG4-related lymphadenopathy with pericardial and periarterial involvement.

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No association of chronic obstructive pulmonary disease with abdominal aortic aneurysm growth

Abstract

Chronic obstructive pulmonary disease (COPD) is independently and positively associated with abdominal aortic aneurysm (AAA) presence. The aim of the present article was to determine whether COPD is associated with AAA growth. We reviewed currently available studies with a systematic literature search and meta-analytic estimate. Databases including MEDLINE and EMBASE were searched through July 2015 using Web-based search engines (PubMed and OVID). Studies considered for inclusion met the following criteria: the study population was AAA patients with and without COPD; and outcomes included data regarding AAA growth. For each study, growth rates in both the COPD and non-COPD groups were used to generate standardized mean differences (SMDs) and 95 % confidence intervals (CIs). Of 614 potentially relevant publications screened initially, we identified 10 eligible studies including data on a total of 2663 AAA patients. None of them demonstrated a statistically significant (positive or negative) association of COPD with AAA growth rates. A pooled analysis demonstrated that COPD is not associated with AAA growth rates (SMD, 0.04; 95 % CI, –0.07 to 0.15; p = 0.50). There was no evidence of significant publication bias. In conclusion, we found that COPD is not associated with AAA growth. Further investigations would be required to elucidate why COPD is not associated with AAA growth despite its positive association with AAA presence.

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Four cases of investigational therapy with interleukin-11 against acute myocardial infarction

Abstract

We describe four cases of the patients with ST-elevation myocardial infarction (STEMI) that were treated with interleukin-11 (IL-11), a cardioprotective cytokine. Recombinant human IL-11 (rhIL-11), was intravenously administered to two cases at low dose (6 µg/kg) and to two at high dose (25 µg/kg). The cytokine administration started just after the coronary occlusion was confirmed by coronary angiography (CAG), taking 3 h. Following CAG, percutaneous coronary intervention (PCI) was performed as a standard therapy. No serious adverse drug reactions were observed. All the cases left the hospital without the symptom of heart failure. We discuss the possibility of the clinical use of rhIL-11 as an adjunct therapy to PCI for the STEMI patients.

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Meeting report on “Animal Evolution: New Perspectives From Early Emerging Metazoans”, Tutzing, September 14–17, 2015

This recent meeting covered non-bilaterian (e.g., cnidarians, ctenophores, and sponges) animals broadly, but with emphasis in four areas: 1) New genomic resources and tools for functional studies, 2) advances in developmental and regeneration studies, 3) the evolution and function of nervous systems, 4) symbiosis and the holobiome.

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Human and primate-specific microRNAs in cancer: Evolution, and significance in comparison with more distantly-related research models

The largest proportion of microRNAs in humans (ca. 40–50%) originated in the phylogenetic grouping defined as primates. The dynamic evolution of this family of non-coding RNA is further demonstrated by the presence of microRNA unique to the human species. Investigations into the role of microRNA in cancer have until recently mainly focused on the more ancient members of this RNA family that are widely conserved in the animal kingdom. As I describe in this review the evolutionary young lineage and species-specific microRNA could be important contributors to cancers, especially in particular organs in primates compared to more distantly-related research models. Elucidating the biological significance of primate and human-specific microRNA in cancer could have important implications for cancer research and the use of non-primate animal models.

The human miRNAome can be divided into miRNAs that are widely conserved, those that are primate-specific, and those that are human-specific. The latter two categories can also contribute to tumor development and complicate the study of human cancers in non-primate animal models.

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IJMS, Vol. 17, Pages 146: Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts

Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) in vivo and in angiotensin II (Ang II)–treated renal fibroblast NRK-49F cells in vitro. Our data showed that UUO induced renal fibrosis and combined with the activation of ERK signaling, the upregulation of fibronectin, collagen I, and transforming growth factor-β (TGF-β). The administration of metformin inhibited the activation of ERK signaling and attenuated the production of extracellular matrix (ECM) proteins and collagen deposition in the obstructed kidneys. In cultured renal fibroblasts, Ang II increased the expression of fibronectin and collagen I and also activated ERK signaling and TGF-β in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II–induced ERK signaling activation and ECM overproduction. Our results show that metformin prevents renal fibrosis, possibly through the inhibition of ERK signaling, and may be a novel strategy for the treatment of renal fibrosis.

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IJMS, Vol. 17, Pages 148: Biodegradable Polymers Influence the Effect of Atorvastatin on Human Coronary Artery Cells

Drug-eluting stents (DES) have reduced in-stent-restenosis drastically. Yet, the stent surface material directly interacts with cascades of biological processes leading to an activation of cellular defense mechanisms. To prevent adverse clinical implications, to date almost every patient with a coronary artery disease is treated with statins. Besides their clinical benefit, statins exert a number of pleiotropic effects on endothelial cells (ECs). Since maintenance of EC function and reduction of uncontrolled smooth muscle cell (SMC) proliferation represents a challenge for new generation DES, we investigated the effect of atorvastatin (ATOR) on human coronary artery cells grown on biodegradable polymers. Our results show a cell type-dependent effect of ATOR on ECs and SMCs. We observed polymer-dependent changes in IC50 values and an altered ATOR-uptake leading to an attenuation of statin-mediated effects on SMC growth. We conclude that the selected biodegradable polymers negatively influence the anti-proliferative effect of ATOR on SMCs. Hence, the process of developing new polymers for DES coating should involve the characterization of material-related changes in mechanisms of drug actions.

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IJMS, Vol. 17, Pages 147: Cell Therapy Using Bone Marrow-Derived Stem Cell Overexpressing BMP-7 for Degenerative Discs in a Rat Tail Disc Model

Degenerative discs can cause low back pain. Cell-based transplantation or growth factors therapy have been suggested as a strategy to stimulate disc regeneration. Bone marrow-derived mesenchymal stem cells (BMDMSC) containing bone morphogenetic protein-7 (BMP-7) gene were constructed. We evaluated the effectiveness of these BMP-7 overexpressing cells on degenerative discs in rat tails. In vitro and in vivo studies were designed. In the first stage, the rats were divided into two group according to discs punctured by different needle gauges (18 gauge and 22 gauge). In the second stage, the ideal size of needle was used to induce rat tail disc degeneration. These animals are divided into three groups according to timing of treatment (zero-week, two-week, four-week). Each group was divided into three treating subgroups: control group, BMDMSC group, and Baculo-BMP-7-BMDMSC group. Each rat undergoes radiography examination every two weeks. After eight weeks, the discs were histologically examined with hematoxylin and eosin stain and Alcian blue stain. The 18-gauge group exhibited significant decrease in disc height index (%) than 22-gauge group at eight weeks at both Co6-7 (58.1% ± 2.8% vs. 63.7% ± 1.0%, p = 0.020) and Co8-9 discs (62.7% ± 2.8% vs. 62.8% ± 1.5%, p = 0.010). Baculo-BMP-7-BMDMSCs group showed significant difference in disc height index compared to the BMDMSCs group at both Co6-7 (93.7% ± 1.5% vs. 84.8% ± 1.0%, p = 0.011) and Co8-9 (86.0% ± 2.1% vs. 81.8% ± 1.7%, p = 0.012). In Baculo-BMP-7-BMDMSCs group, the zero-week treatment subgroup showed significant better in disc height index compared to two-week treatment group (p = 0.044), and four-week treatment group (p = 0.011). The zero-week treatment subgroup in Baculo-BMP-7-BMDMSCs group also had significant lower histology score than two-week treatment (4.3 vs. 5.7, p = 0.045) and four-week treatment (4.3 vs. 6.0, p = 0.031). In conclusion, Baculo-BMP-7-BMDMSC can slow down the progression of disc degeneration, but could not provide evidence of regeneration. Early treatment might obtain more distinct results.

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Ultrasonography versus computed tomography for initial investigation of suspected nephrolithiasis

Review Articles
Katie Lin, Shawn Dowling
Canadian Journal of Emergency Medicine,FirstView Article(s), 4 pages

Abstract


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Secular trends in family dinner frequency among adolescents

Eating meals, particularly dinner, with family members has been found to be associated with improved dietary intake, lower prevalence of disordered eating behaviors, lower levels of substance abuse, and improv...

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Influence of essential amino acids on muscle mass and muscle strength in patients with cerebral stroke during early rehabilitation: protocol and rationale of a randomized clinical trial (AMINO-Stroke Study)

Patients with stroke are at a high risk for long-term handicap and disability. In the first weeks after stroke muscle wasting is observed frequently. Early post-stroke rehabilitation programs are directed to i...

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Toxins, Vol. 8, Pages 32: Differential Properties of Venom Peptides and Proteins in Solitary vs. Social Hunting Wasps

The primary functions of venoms from solitary and social wasps are different. Whereas most solitary wasps sting their prey to paralyze and preserve it, without killing, as the provisions for their progeny, social wasps usually sting to defend their colonies from vertebrate predators. Such distinctive venom properties of solitary and social wasps suggest that the main venom components are likely to be different depending on the wasps' sociality. The present paper reviews venom components and properties of the Aculeata hunting wasps, with a particular emphasis on the comparative aspects of venom compositions and properties between solitary and social wasps. Common components in both solitary and social wasp venoms include hyaluronidase, phospholipase A2, metalloendopeptidase, etc. Although it has been expected that more diverse bioactive components with the functions of prey inactivation and physiology manipulation are present in solitary wasps, available studies on venom compositions of solitary wasps are simply too scarce to generalize this notion. Nevertheless, some neurotoxic peptides (e.g., pompilidotoxin and dendrotoxin-like peptide) and proteins (e.g., insulin-like peptide binding protein) appear to be specific to solitary wasp venom. In contrast, several proteins, such as venom allergen 5 protein, venom acid phosphatase, and various phospholipases, appear to be relatively more specific to social wasp venom. Finally, putative functions of main venom components and their application are also discussed.

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Toxins, Vol. 8, Pages 33: Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice

Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT3 (MDL-72222, 15 μg) receptor antagonist, but not with α2-adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain.

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Toxins, Vol. 8, Pages 34: Roles of Anthrax Toxin Receptor 2 in Anthrax Toxin Membrane Insertion and Pore Formation

Interaction between bacterial toxins and cellular surface receptors is an important component of the host-pathogen interaction. Anthrax toxin protective antigen (PA) binds to the cell surface receptor, enters the cell through receptor-mediated endocytosis, and forms a pore on the endosomal membrane that translocates toxin enzymes into the cytosol of the host cell. As the major receptor for anthrax toxin in vivo, anthrax toxin receptor 2 (ANTXR2) plays an essential role in anthrax toxin action by providing the toxin with a high-affinity binding anchor on the cell membrane and a path of entry into the host cell. ANTXR2 also acts as a molecular clamp by shifting the pH threshold of PA pore formation to a more acidic pH range, which prevents premature pore formation at neutral pH before the toxin reaches the designated intracellular location. Most recent studies have suggested that the disulfide bond in the immunoglobulin (Ig)-like domain of ANTXR2 plays an essential role in anthrax toxin action. Here we will review the roles of ANTXR2 in anthrax toxin action, with an emphasis on newly updated knowledge.

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Publications Received for Review

Phonetica 2015;72:273

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Cortical Damage and Disability in Multiple Sclerosis: Relation to Intracortical Inhibition and Facilitation

Publication date: Available online 21 January 2016
Source:Brain Stimulation
Author(s): Julia C. Nantes, Jidan Zhong, Scott A. Holmes, Sridar Narayanan, Yves LaPierre, Lisa Koski
BackgroundMultimodal research combining biomarkers of intracortical activity and cortical damage could shed light on pathophysiological and adaptive neural processes related to the clinical severity of neurological conditions such as multiple sclerosis (MS).ObjectiveAmong people with relapsing-remitting and progressive forms of MS, we assessed the extent to which transcranial magnetic stimulation (TMS)-based biomarkers of excitatory and inhibitory cortical activity are related to cortical damage and clinical impairment.MethodsParticipants included 18 healthy individuals and 36 people with MS who had a relapsing-remitting or progressive clinical course. Using TMS, intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and cortical silent period (CSP) were obtained. Cortical volume and cortical magnetization transfer ratio (MTR) were quantified. Disability was assessed with Multiple Sclerosis Functional Composite (MSFC).ResultsLower mean MTR within the cerebral cortex correlated with shorter CSP among MS participants with a progressive, but not a relapsing-remitting, clinical course. Within the cortical hand knob region targeted with the TMS, lower MTR was correlated with lower SICI only among individuals with relapsing-remitting MS. Longer CSP, higher ICF, lower cortical MTR, and sex were all independent significant predictors of poor upper extremity motor performance, while only cortical MTR was a significant independent predictor of total MSFC score among people with MS.ConclusionsCortical damage and cortical activity (both inhibitory and excitatory) may contribute to the severity of motor disability experienced by people with MS. When interpreting TMS-based outcomes, cortical integrity, clinical course, and symptom type should be considered.



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MAVIN: An Open-Source Tool for Interactive Analysis and Visualization of EMG Data

Publication date: Available online 21 January 2016
Source:Brain Stimulation
Author(s): Christopher R. Mullins, Colleen A. Hanlon




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Endogenous Action Selection Processes in Dorsolateral Prefrontal Cortex Contribute to Sense of Agency: a Meta-Analysis of tDCS Studies of ‘Intentional Binding’

Publication date: Available online 21 January 2016
Source:Brain Stimulation
Author(s): Nima Khalighinejad, Steven Di Costa, Patrick Haggard
Backgroundsense of agency is the experience of being in control of one's own actions and their consequences. The role of frontal cortex in this aspect of action control and awareness remains unclear.Objective/Hypothesis: given the role of dorsolateral prefrontal cortex (DLPFC) in action selection, we predicted that DLPFC may contribute to sense of agency when participants select between multiple actions.Methodswe performed a series of experiments, manipulating a range of task parameters related to action selection and action outcomes, while participants were exposed to tDCS stimulation of the left DLPFC. We measured the temporal association between a voluntary action and its outcome using the intentional binding effect, as an implicit measure of sense of agency.ResultsFixed-effect meta-analysis of our primary data showed a trend towards a frontal tDCS, together with considerable heterogeneity between our experiments. Classifying the experiments into subsets of studies, according to whether participants endogenously selected between alternative actions or not, explained 71% of this heterogeneity. Anodal stimulation of DLPFC increased the temporal binding of actions towards tones in the subset of studies involving endogenous action selection, but not in the other studies.ConclusionsDLPFC may contribute to sense of agency when participants selected between multiple actions. This enhanced feeling of control over voluntary actions could be related to the observed therapeutic effects of frontal tDCS in depression.



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Porous Organic Cage Thin Films and Molecular-Sieving Membranes

Porous organic cage molecules are fabricated into thin films and molecular-sieving membranes. Cage molecules are solution cast on various substrates to form amorphous thin films, with the structures tuned by tailoring the cage chemistry and processing conditions. For the first time, uniform and pinhole-free microporous cage thin films are formed and demonstrated as molecular-sieving membranes for selective gas separation.

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Adaptive self-organizing organisms using a bio-inspired gene regulatory network controller: for the aggregation of evolutionary robots under a changing environment

This work has explored the adaptive potential of simulated swarm robots that contain a genomic encoding of a bio-inspired gene regulatory network (GRN). An artificial genome is combined with a flexible agent-based system, representing the activated part of the regulatory network that transduces environmental cues into phenotypic behavior. Using an Alife simulation framework that mimics a changing environment, we have shown that separating the static from the conditionally active part of the network contributes to a better adaptive behavior. This chapter describes the biologically inspired concept of GRNs to develop a distributed robot self-organizing approach. In particular, it shows that by using this approach, multiple swarm robots can aggregate to form a robotic organism that can adapt its configuration as a response to a dynamically changing environment. In addition, through the comparison of several different simulation experiments, the results illustrate the impact of evolutionary operators such as mutations and duplications on improving the adaptability of organisms.

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Saccharification protocol for small-scale lignocellulosic biomass samples to test processing of cellulose into glucose

Second generation biofuels are derived from inedible lignocellulosic biomass of food and non-food crops. Lignocellulosic biomass is mainly composed of cell walls that contain a large proportion of cellulosic and hemicellulosic polysaccharides. An interesting route to generate biofuels and bio-based materials is via enzymatic hydrolysis of cell wall polysaccharides into fermentable sugars, a process called saccharification. The released sugars can then be fermented to fuels, e.g. by use of yeast. To test the saccharification efficiency of lignocellulosic biomass on a lab-scale, a manual saccharification protocol was established that uses only small amounts of biomass and a low concentration of enzyme. This protocol can be used for different plant species like Arabidopsis thaliana, tobacco, maize and poplar. The low enzyme concentrations make it possible to detect subtle improvements in saccharification yield and to analyze the speed of hydrolysis. Although a specific acid and alkali pretreatment were included, the saccharification step can be preceded by any other pretreatment. Because no advanced equipment is necessary, this protocol can be carried out in many laboratories to analyze saccharification yield. The protocol was initially described in Van Acker et al. (2013).

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Polynomial chaos and Bayesian inference in stochastic electroencephalography

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The development and use of evidence-based instruments to measure quality of life and enhance organisational performance

Aim: As the concept of quality of life (QOL) evolved there came a need for a systematic approach to the assessment of domain-referenced quality of life outcomes. It is important to understand the context within which the QOL concept is used. This presentation describes the framework to conceptualise and measure QOL, provides an example of a QOL questionnaire based on current measurement best practices and demonstrates how evidence based QOL instruments are used to enhance organisational performance. Methods: The development of the Personal Outcomes Scale (POS) provides an example of a QOL questionnaire based on current measurement best practices. Examples are given of how the POS and other instruments are used. Results: A thorough research process resulted in a solid instrument to measure the QOL of people with ID in terms of support outcomes. The POS provides information on actions to enhance an individual's well-being and contributes to evidence-based use of quality of life data. Evidence based QOL instruments are used in several ways in enhancing organisational performance. Conclusion: The development of the POS, with data on reliability and validity, and the availability of more QOL measurement instruments, set the stage for use of evidence based work in enhancing organisational performance.

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The impact of human and social capital on entrepreneurs' knowledge of finance alternatives

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Chronicle: representation of complex time structures

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Towards an evolutionary model of the entrepreneurial financing process: insights from biotechnology startups

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Incremental Financing Decisions in High-Growth Companies: Pecking Order and Debt Capacity Considerations

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Venture capitalists' selection process: the case of biotechnology proposals

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ASLK: uitdagingen voor het partnership tussen overheid en privé

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Welke toekomst hebben de Belgische openbare kredietinstellingen?

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Aandelenbezit door banken

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Protection against oxidative stress-induced apoptosis in kidney epithelium by Angelica and Astragalus

Publication date: 17 February 2016
Source:Journal of Ethnopharmacology, Volume 179
Author(s): Muhammad Shahzad, David M. Small, Christudas Morais, Ken Wojcikowski, Arham Shabbir, Glenda C. Gobe
Ethnopharmacological relevanceAstragalus membranaceus either alone or in combination with Angelica sinensis has been used traditionally for kidney disease in East Asia and China for thousands of years. Previous studies using in vivo animal models have shown the benefits of these medicinal herbs in kidney diseases that involve oxidative stress. However, the mechanisms by which these medicinal herbs protect kidney cells remain largely unknown.Aim of the studyTo investigate the mechanisms by which ethanol, methanol and aqueous crude extracts of roots of A. membranaceus and A. sinensis afford protection to human kidney proximal tubular epithelial cells, using an in vitro model of oxidative stress.Materials and methodsEthanol, methanol and aqueous extracts of roots of A. membranaceus and A. sinensis were prepared by a three-solvent sequential process. HK2 human kidney proximal tubular epithelial cells were treated with H2O2 alone (0.5mM) or in combination with different concentrations of extracts. Cell mitosis and death (microscopy) and cell viability (MTT assay) were compared. Western immunoblot was used to study expression of apoptosis-related proteins (pro-apoptotic Bax andanti-apoptotic Bcl-XL), and cell survival (NFκB subunits p65 and p50), pro-inflammatory (TNF-α) and protective (TGFβ1) proteins.ResultsH2O2-induced oxidative stress significantly increased apoptosis and reduced cell survival; upregulated pro-apoptotic and down-regulated Bcl-XL; increased NFκB (p65, p50); increased TNFα and decreased TGFβ1. All changes indicated kidney damage and dysfunction. All were modulated by all extracts of both plant species, except for NFκB which was only modulated by extracts of A. membranaceus.ConclusionsIn conclusion, in a model of oxidative stress that might occur after nephrotoxicity, the plant extracts were protective via anti-apoptotic and anti-inflammatory mechanisms.

Graphical abstract

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Antinociceptive activity of the essential oil from Artemisia ludoviciana

Publication date: 17 February 2016
Source:Journal of Ethnopharmacology, Volume 179
Author(s): Gerardo D. Anaya-Eugenio, Isabel Rivero-Cruz, Robert Bye, Edelmira Linares, Rachel Mata
Ethnopharmacological relevanceAerial parts of Artemisia ludoviciana are widely used in Mexico for treating gastrointestinal disorders, painful complaints and diabetes.Aim of the studyTo establish the preclinical efficacy as antinociceptive agent of the essential oil (EO) from the aerial parts of A. ludoviciana using well-known animal models.Materials and methodsAcute antinociceptive effect of EO (1, 10, 31.6, 100, and 316mg/kg, i.p.) was evaluated using the hot plate and paw formalin models in mice. The motor effects were assessed with the rota-rod and open field assays. The volatile components obtained by headspace solid phase microextraction (HS-SPME) and hydrodistillation were determined using gas chromatography coupled with mass spectrometry (GC–MS) analysis.ResultsEO decreased first and second phases of formalin test; in the first stage, the better effect was obtained with the treatment of 316mg/kg but in the second phase, time licking was attenuated at the doses of 31.6, 100 and 316mg/kg. The effectiveness of EO (ED50=25.9mg/kg) for attenuating neurogenic pain was corroborated using the hot plate test. The antinociceptive action of EO was blocked by naloxone suggesting that its mode of action involved an opioid mechanism. Furthermore, EO (316mg/kg) did not affect animal motor and coordination functions when tested by the rota-rod and open field tests. The latter results indicated that the pharmacological effects exerted by EO during the hot plate and formalin test are truly antinociceptive. GC–MS analysis of EO revealed that (±)-camphor, γ-terpineol, 1,8-cineole and borneol were the major volatile compounds of the plant.ConclusionEO from A. ludoviciana showed significant antinociceptive effect, which appeared to be partially mediated by the opioid system. These findings could support the long-term use of A. ludoviciana for treating painful complaints in Mexican folk medicine.

Graphical abstract

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Medicinal plants used in Mexican traditional medicine for the treatment of colorectal cancer

Publication date: 17 February 2016
Source:Journal of Ethnopharmacology, Volume 179
Author(s): Nadia J. Jacobo-Herrera, Frida E. Jacobo-Herrera, Alejandro Zentella-Dehesa, Adolfo Andrade-Cetto, Michael Heinrich, Carlos Pérez-Plasencia
Ethnopharmacological relevanceCancer cases numbers are increasing worldwide positioning this disease as the second cause of mortality for both sexes. Medicinal plants have been used in the fight against cancer as the basis for drug discovery and nowadays more than 70% of anticancer drugs have a natural origin. Mexico is regarded for its cultural and biological diversity, which is reflected in the vast traditional knowledge of herbal remedies. In this review we examined herbal remedies employed in colorectal cancer treatment (CRC).Aim of the studyThe goal of this work was to gather scientific reports of plants used in Mexican traditional medicine for CRC treatment.Materials and methodsWe performed a search on scientific literature databases using as keywords: "colon cancer", "gastric cancer", "cytotoxicity", studies "in vitro and in vivo", in combination with "Mexican medicinal plants" or "Mexican herbal remedies". The selection criteria of cytotoxic activity for extracts or pure compounds was based on the National Cancer Institute of USA recommendations of effective dose 50 (ED50) of ≤20μg/mL and ≤4μg/mL, respectively.ResultsIn this review we report 25 botanic families and 39 species of plants used for the treatment of colon cancer in Mexico with evidence in studies in vitro and in vivo.ConclusionsMedicinal plants are still a great source of novel chemical structures with antineoplastic potential as it is proven in this work. The selection criteria and activity was narrowed for methodological purposes, nevertheless, drug discovery of natural origin continues to be a highly attractive R&D strategy.

Graphical abstract

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IFC (Journal of Ethnopharmacology)

Publication date: 3 February 2016
Source:Journal of Ethnopharmacology, Volume 178





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Blunt aortic injury: risk factors and impact of surgical approaches

Abstract

Purpose

This study reviews our 17-year experience of managing blunt traumatic aortic injury (BTAI).

Methods

We analyzed information collected retrospectively from a tertiary trauma center.

Results

Between October 1995 and June 2012, 88 patients (74 male and 14 female) with a mean age of 39.9 ± 17.9 years (range 15–79 years) with proven BTAI were enrolled in this study. Their GCS, ISS, and RTS scores were 12.9 ± 3.7, 29.2 ± 9.8, and 6.9 ± 1.4, respectively. Twenty-one (23.8 %) patients were managed non-operatively, 49 (55.7 %) with open surgical repair, and 18 (20.5 %) with endovascular repair. The in-hospital mortality rate was 17.1 % (15/81) and there were no deaths in the endovascular repair group. The mean follow-up period was 39.9 ± 44.2 months. The survivors of blunt aortic injury had lower ISS, RTS, TRISS, and serum creatinine level and lower rate of massive blood transfusion, shock, and intubation than the patients who died, despite higher rates of endovascular repair, hemoglobin, and GCS on presentation. The degree of aortic injury, different therapeutic options, GCS, shock presentation, and intubation on arrival all had significant impacts on outcome.

Conclusions

Shock, aortic injury severity, coexisting trauma severity, and different surgical approaches impact survival. Endovascular repair achieves a superior mid-term result and is a reasonable option for treating BTAI.

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Transumbilical cord access (TUCA) for laparoscopy in infants and children: simple, safe and fast

Abstract

Purpose

We herein report a case series evaluating the safety and complication rate of transumbilical cord access (TUCA) for pediatric laparoscopic surgery.

Methods

Data were collected for 556 infants and children. Access into the abdominal cavity was gained via a transverse infraumbilical stab incision passing the fibrotic umbilical cord remnant. Ninety-two infants underwent laparoscopic pyloromyotomy (LPM), 159 female infants underwent herniorrhaphy (LHR) and 309 infants underwent appendectomy (LAP). Of the total operations, 70 % were performed by board-certified surgeons and 30 % were performed by non-board-certified surgeons. The median time of follow-up was 24 months.

Results

No cases of acute severe bleeding or organ laceration were noted. TUCA-related complications were observed in nine patients (1.6 %). Omphalitis and persistent wound secretion were detected in eight children and foreign bodies consisting of cyanoacrylate were removed from three of these patients. Meanwhile, umbilical pain leading to surgical revision was observed in one child, and eight umbilical hernias were repaired during the TUCA procedures. No signs of postoperative incisional hernia were recorded.

Conclusions

TUCA is a safe and comfortable access method for pediatric laparoscopic surgery in various age groups. This method is easy to learn and can be quickly and safely performed in the vast majority of children.

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Surgical intervention strategy for postoperative chylothorax after lung resection

Abstract

Purpose

The optimal surgical management of postoperative chylothorax has not been established. Thus, we evaluated the treatment strategy for postoperative chylothorax and identified associated predictors of surgical intervention.

Methods

The subjects of this retrospective study were 50 patients who suffered postoperative chylothorax, representing 4 % of 1235 patients who underwent pulmonary resection between 2008 and 2012. The chylothorax patients were classified into two groups based on their postoperative management: a conservative group and a surgical group. The following parameters were investigated to establish the predictors of surgical intervention for chylothorax: mode of surgery, preoperative complications, intraoperative management, and postoperative clinical status.

Results

Forty-one (82 %) patients were treated conservatively and 9 (18 %) underwent reoperation, as direct or concomitant ligation of the thoracic duct at the point of leakage. The frequency of postoperative chest tube drainage just after initial surgery was significantly greater in the surgical group than the conservative group before oral intake was restarted (448 ± 189 vs. 296 ± 117 ml/12 h, respectively; p = 0.003). Furthermore, it was a significant predictor of reoperation based on a multivariate analysis (p = 0.010).

Conclusions

The amount of chest tube drainage just after surgery and before oral intake was a useful predictor to help us decide on the need for early surgical intervention for postoperative chylothorax.

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