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Attaching and effacing bacterial pathogens attach to the apical surface of epithelial cells and disrupt epithelial barrier function, increasing permeability and allowing luminal contents access to the underlying milieu. Previous in vitro studies demonstrated that the neuropeptide vasoactive intestinal peptide (VIP) regulates epithelial paracellular permeability, and the high concentrations and close proximity of VIP-containing nerve fibers to intestinal epithelial cells would support such a function in vivo. The aim of this study was to examine whether VIP treatment modulated Citrobacter rodentium-induced disruption of intestinal barrier integrity and to identify potential mechanisms of action. Administration of VIP had no effect on bacterial attachment although histopathological scoring demonstrated a VIP-induced amelioration of colitis-induced epithelial damage compared with controls. VIP treatment prevented the infection-induced increase in mannitol flux a measure of paracellular permeability, resulting in levels similar to control mice, and immunohistochemical studies demonstrated that VIP prevented the translocation of tight junction proteins: zonula occludens-1, occludin, and claudin-3. Enteropathogenic Escherichia coli (EPEC) infection of Caco-2 monolayers confirmed a protective role for VIP on epithelial barrier function. VIP prevented EPEC-induced increase in long myosin light chain kinase (MLCK) expression and myosin light chain phosphorylation (p-MLC). Furthermore, MLCK inhibition significantly attenuated bacterial-induced epithelial damage both in vivo and in vitro. In conclusion, our results indicate that VIP protects the colonic epithelial barrier by minimizing bacterial-induced redistribution of tight junction proteins in part through actions on MLCK and MLC phosphorylation.

Saccharomyces boulardii has received increasing attention as a probiotic effective in the prevention and treatment of infectious and inflammatory bowel diseases. The aim of this study was to examine the ameliorating effects of S. boulardii on Citrobacter rodentium colitis in vivo and identify potential mechanisms of action. C57BL/6 mice received 2.5 × 108C. rodentium by gavage on day 0, followed by S. boulardii (25 mg; 5 × 108live cells) gavaged twice daily from day 2 to day 9. Animal weights were monitored until death on day 10. Colons were removed and assessed for epithelial barrier function, histology, and myeloperoxidase activity. Bacterial epithelial attachment and type III secreted proteins translocated intimin receptor Tir (the receptor for bacterial intimin) and EspB (a translocation apparatus protein) required for bacterial virulence were assayed. In infected mice, S. boulardii treatment significantly attenuated weight loss, ameliorated crypt hyperplasia (234.7 ± 7.2 vs. 297.8 ± 17.6 μm) and histological damage score (0.67 ± 0.67 vs. 4.75 ± 0.75), reduced myeloperoxidase activity (2.1 ± 0.4 vs. 4.7 ± 0.9 U/mg), and attenuated increased mannitol flux (17.2 ± 5.0 vs. 31.2 ± 8.2 nm·cm−2·h−1). The ameliorating effects of S. boulardii were associated with significantly reduced numbers of mucosal adherent C. rodentium, a marked reduction in Tir protein secretion and translocation into mouse colonocytes, and a striking reduction in EspB expression and secretion. We conclude that S. boulardii maintained colonic epithelial barrier integrity and ameliorated inflammatory sequelae associated with C. rodentium infection by attenuating C. rodentium adherence to host epithelial cells through putative actions on the type III secretion system.

A novel series of conformationally-restricted oxazolidinones was synthesized which possess a fused pyrazole ring substituted with various alkyl, aryl and heteroaryl substituents. A number of analogs exhibited potent activity against both Gram-positive and fastidious Gram-negative organisms.

A series of 3-aminoquinazolinediones was synthesized and evaluated for its antibacterial and DNA gyrase activity. The SAR around the quinazolinedione core was explored and the optimal substitutions were combined to give two compounds, 2r and 2s , with exceptional enzyme potency (IC 50 = 0.2 μM) and activity against Gram-positive organisms (MIC’s = 0.015–0.06 μ g/mL).

Guillain-Barré syndrome (GBS) is an immune-mediated inflammatory disorder of the peripheral nervous system (PNS). Experimental autoimmune neuritis (EAN) is a useful animal model for studying GBS. Currently, GBS remains a life-threatening disorder and more effective therapeutic strategies are in urgent need.Accumulating evidence has revealed that T helper (Th) 17 cells and their cytokines are pathogenic in GBS/EAN. Drugs attenuated clinical signs of GBS/EAN, in part, by decreasing Th17 cells or IL-17A. Th17 cells and their cytokines might be potential therapeutic targets. Approaches targeting Th17 cells or their cytokines are in development in treating Th17 cells-involved disorders. In this review, we summarize the up-to-date knowledge on roles of Th17 cells and their cytokines in GBS/EAN, as well potential approaches targeting Th17 cells and their cytokines as clinical applications.As Th17 cells produce different sets of pro-inflammatory cytokines and Th17-related cytokines are not exclusively produced by Th17 cells, targeting Th17 cell development may be superior to blocking a single Th17 cytokine to treat Th17 cells-involved disorders. Considering the essential role of retinoic acid-related orphan receptor γT (RORγT) and IL-23 in Th17 cell development, RORγT inhibitors or IL-23 antagonists may provide better clinical efficacy in treating GBS/EAN.

To enable an investigation of pharmacokinetics and tissue distribution of Aucubin, Ajugol and Catalpol in rats, a high-performance liquid chromatography-electro spray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed for the simultaneous quantitative determination of the three compounds. Biological samples were prepared by a simple protein precipitation with methanol (containing 0.05% formic acid). The analytes were separated by a C18 reversed phase column and detected with a triple quadrupole tandem mass spectrometer in the multiple-reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 364.3→149.0 for Aucubin, m/z 366.5→151.1 for Ajugol, m/z 380.0→183.3 for Catalpol and m/z 530.3→183.1 for Picroside-II (IS) in positive ionization. Good linearity of each calibration curve was produced over the concentration range of 1-1000ng/mL. The lower limit of quantification (LLOQ) was 1ng/mL for the three analytes. This method was successfully applied to the pharmacokinetic and tissue distribution studies of Aucubin, Ajugol and Catalpol in rat. The current results revealed pharmacokinetic behaviors of the herb compound and provided novel evidence of the presence of Aucubin and Catalpol in rat brain. The acquired data would be helpful for the clinical application and further studies of Traditional Chinese Medicines (TCM) with active ingredients of Iridoid Glycosides.

Many studies have investigated the association between serum/hair zinc levels and breast cancer, but the results were inconsistent. To compare the serum and hair zinc levels in women with breast cancer and controls, we conducted a systematic literature search of PubMed, Web of Science, Cochrane Library and Embase to identify relevant studies with publication dates up through November 2014. Based on a random effects model, summary standard mean differences (SMDs) and the corresponding 95% confidence intervals (CIs) were used to compare the serum and hair zinc levels in women with breast cancer and controls. Fourteen studies that investigated serum zinc levels and seven studies that assessed hair zinc levels were included. Our study observed no difference in serum zinc levels between breast cancer cases and controls (SMD (95%CI): −0.65[−1.42,0.13]). However, we determined that hair zinc levels were lower in women with breast cancer compared with those of controls (SMD (95%CI): −1.99[−3.46, −0.52]). In conclusion, this study was the first to provide evidence that hair zinc levels in female breast cancer patients are lower than in controls; however, there was no significant difference in serum zinc levels between female breast cancer patients and controls.

Right-to-left shunt (RLS) is associated with cryptogenic stroke and migraine. Herein we investigated the relationship between RLS and silent lacunar infarcts in patients with migraine. A total of 263 patients with migraine who met eligibility criteria were enrolled from January 2010 to December 2011, among which 127 subjects fell into RLS group. Baseline demographics were comparable between RLS and non-RLS groups (P>0.05). The incidence of silent lacunar infarcts in RLS group was not significantly different from that of the non-RLS group (25.2% versus 21.3%,P>0.05). Furthermore, we found that the incidence of silent lacunar infarcts in permanent and latent RLS subgroups was comparable with non-shunt RLS subgroup (28.6% versus 24% versus 21.3%,P>0.05). Similarly, the incidence of silent lacunar infarcts in the non-RLS group, mild-shunt group, and large-shunt group was also comparable (21.3% versus 23.8% versus 29.3%,P>0.05). In addition, RLS did not increase the incidence of silent lacunar infarcts in migraine patients with elder age (P>0.05). In conclusion, RLS does not increase the incidence of silent lacunar infarcts in patients with migraine. Further prospective studies are warranted to validate this finding.

Introduction Guillain-Barré syndrome (GBS) is an immune-mediated disorder of the peripheral nervous system. Respiratory failure requiring mechanical ventilation (MV) is a serious complication of GBS. Identification of modifiable risk factors for MV and poor short-term prognosis in mechanically ventilated patients with GBS may contribute to the individualized management and may help improve the outcome of the patients. Methods We retrospectively analyzed the clinical data of 541 patients who were diagnosed with GBS from 2003 to 2014. Independent predictors for MV and short-term prognosis in mechanically ventilated patients were identified via multivariate logistic regression analysis. Results The mean age was 41.6 years with a male predilection (61.2 %). Eighty patients (14.8 %) required MV. Multivariate analysis revealed that shorter interval from onset to admission (p p p p p p p p Conclusions Clinical predictors of MV and poor short-term prognosis in mechanically ventilated GBS patients were distinct. Add-on use of intravenous corticosteroids was a risk factor for poor short-term prognosis in mechanically ventilated patients with a nadir MRC sum score from 0 to 12 points.

The current study was to examine the underlying mechanisms responsible for the role of mammalian target of rapamycin (mTOR) in regulating bone cancer-evoked pain and the tolerance of systemic morphine. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats and this evoked significant mechanical and thermal hyperalgesia. Our results showed that the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1), p70 ribosomal S6 protein kinase 1 (S6K1) as well as phosphatidylinositide 3-kinase (p-PI3K) pathways were amplified in the superficial dorsal horn of the spinal cord of bone cancer rats compared with control rats. Blocking spinal mTOR by using rapamycin significantly attenuated activities of PI3K signaling pathways as well as mechanical and thermal hyperalgesia. Additionally, rapamycin enhanced attenuations of protein kinase Cɛ (PKCɛ)/protein kinase A (PKA) induced by morphine and further extended analgesia of morphine via µ-opioid receptor (MOR). Our data for the first time revealed specific signaling pathways leading to bone cancer pain, including the activation of mTOR and PI3K and downstream PKCɛ/PKA, and resultant sensitization of MOR. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of bone cancer pain often observed in clinics.

Background Diet is the primary way cadmium (Cd) enters the body in those without occupational exposure and who do not inhabit Cd-polluted regions. Findings on the relationship between dietary Cd exposure and breast cancer (BC) risk have been inconsistent; a meta-analysis has supported this association but 2 recent cohort studies showed inconsistent results. Hence, we performed an updated meta-analysis to re-evaluate the association between dietary Cd exposure and BC risk. Material/Methods We searched PubMed, Medline, and EMBASE to identify relevant studies published through September 2014. Combined relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were used to assess the association between dietary Cd exposure and BC risk. Results We identified 6 studies involving 321 315 participants and 11 978 cases. Our study suggested there was no statistically significant positive association between dietary Cd exposure and BC risk, the combined RR and corresponding 95% CI was 1.01 [0.88, 1.14]. The result was not modified by menopause status, geographic area, or study design. Conclusions Our study did not find a statistically significant positive association between dietary Cd exposure and BC risk. It is necessary to investigate this relationship among the high-risk groups and more cohort studies based on diverse populations are needed.

Acute necrotizing encephalopathy (ANE) is a rare but distinctive type of acute encephalopathy with global distribution. Occurrence of ANE is usually preceded by a virus-associated febrile illness and ensued by rapid deterioration. However, the causal relationship between viral infections and ANE and the exact pathogenesis of ANE remain unclear; both environmental and host factors might be involved. Most cases of ANE are sporadic and nonrecurrent, namely, isolated or sporadic ANE; however, few cases are recurrent and with familial episodes. The recurrent and familial forms of ANE were found to be incompletely autosomal-dominant. Further the missense mutations in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2) were identified. Although the clinical course and the prognosis of ANE are diverse, the hallmark of neuroradiologic manifestation of ANE is multifocal symmetric brain lesions which are demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI). The treatment of ANE is still under investigation. We summarize the up-to-date knowledge on ANE, with emphasis on prompt diagnosis and better treatment of this rare but fatal disease.

Objective A potential association between diabetes and Guillain-Barré syndrome (GBS) has been indicated by a few case studies. We retrospectively analyzed the clinical features of a large cohort of GBS patients to explore the relationship between the level of fasting plasma glucose (FPG) obtained in the acute phase at admission and the severity of GBS. Methods Three hundred and four GBS patients were divided into two groups, one with normal FPG and the other with high FPG levels according to the international standards of FPG. Results The GBS disability scale score was positively, the Medical Research Council (MRC) sum score was negatively correlated to the level of FPG, but not to blood HBA1c or CSF glucose concentrations. A relatively higher FPG level was observed in older and younger GBS patients, and more often in those with cranial nerve involvement, autonomic deficit, dyspnea and ventilator dependence than in patients without these clinical characteristics. Importantly, higher levels of FPG at admission were associated with poorer short-term prognosis measured by the MRC sum score and the GBS disability scale at discharge. Conclusions Our data demonstrates that FPG in the acute phase of GBS correlates with the severity of GBS and may predict the short-term prognosis of GBS.

Multiple sclerosis (MS) is an immune-mediated disorder in the central nervous system (CNS) characterized by inflammation and demyelination as well as axonal and neuronal degeneration. So far effective therapies to reverse the disease are still lacking; most therapeutic drugs can only ameliorate the symptoms or reduce the frequency of relapse. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are key players in both mediating immune responses and inducing immune tolerance. Increasing evidence indicates that DCs contribute to the pathogenesis of MS and might provide an avenue for therapeutic intervention. Here, we summarize the immunogenic and tolerogenic roles of DCs in MS and review medicinal drugs that may affect functions of DCs and have been applied in clinic for MS treatment. We also describe potential therapeutic molecules that can target DCs by inducing anti-inflammatory cytokines and inhibiting proinflammatory cytokines in MS.

Reflection-based deep learning, essentially a type of deep learning, aims to promote deep learning by developing reflective learning ability. In order to test "the promoting effects of reflection on deep learning", according to the process model of reflection-based deep learning, we designed the experimental scheme. Firstly, through the pretest questionnaire, we determined the experimental subjects according to their learning capacity level; then through the specific teaching interventions, we guided the experimental class to carry out their reflective learning activities throughout the whole class; finally through variance analysis of the written test and the work creation, we confirmed that the model of reflection-based deep learning had certain feasibility, furthermore the reflection activities really can effectively promote students’ deep learning. Keywords—reflection; reflective learning; deep learning; reflection-based deep learning I. BACKGROUND OF EXPERIMENTAL RESEARCH As early as the mid of 1950s, Marton and Saljo were the first to start the experimental study of deep learning [1]. Around the same period, many other researchers developed the research on deep learning from different perspectives. Through the analysis of deep learning scales developed by Biggs, Entwistle and Ramsden, Nelson Laird and his colleagues found that deep learning can be deconstructed into three component parts: high-order learning, integrative learning, or reflective learning [2]. In other words, all of them are the concrete forms of deep learning. Reflection-based deep learning is mainly about "how to promote deep learning by reflection". Based on lots of literature analysis, we had demonstrated the mutual promotion between deep learning and reflective learning from the theoretical level, and through incorporating the ideas about reflection into the general process of deep learning, constructed the process model of reflection-based deep learning as shown in Figure 1[3]. Now we will put these theories into practice, which is to combine with the relevant courses, design the experimental scheme and develop the teaching activities. Fig. 1. The process model of reflection-based deep learning II. EXPERIMENTAL DESIGN AND IMPLEMENTATION A. Experimental design Deep learning aims to achieve overall learning objectives and develop high-order thinking ability [4]. So is reflectionbased deep learning, which is a special kind of deep learning. As promoting learning is the common character of deep learning and general learning, we can assess deep learning from the traditional point of cognition, motor skills and emotion. Moreover, to develop high-order thinking ability is its particularity, so we also need to measure learnings’ thinking structure level and identify their cognitive development level according to Biggs’ SOLO(Structure of the Observed Learning Outcome) taxonomy. In order to examine the promoting effects of reflection on deep learning, a quasi-experimental study is designed, which has both the experimental group and the compared group at the pre-test and the post-test. And put forward the following three hypotheses: firstly, reflection can help attain the intellectual target of deep learning, especially the high-level cognition of deep knowledge and complex concept; secondly, reflection can promote learnings’ understanding of the problem, and then International Conference on Social Science and Higher Education (ICSSHE 2015) © 2015. The authors Published by Atlantis Press 101 help them get complex learning outcomes and high-level thinking ability; thirdly, reflection can effectively facilitate the learners’ grasp of information technology skills and improve their problem-solving ability and practical-creating ability. B. Experimental implementation In the preparation stage, through the discussion with cooperative teacher, we determine the teaching contents and adjust the teaching plan accordingly. Then in the implementation phase, we observe the two groups’ teaching for eight weeks and properly modify the experimental material. It is composed by pre-test phase, treatment phase, and post-test phase. 1) Pre-test phase In order to ensure the experimental effect, we should choose two classes as similar as possible. According to the outcomes of questionnaire survey and variance analysis, we determine to take class 4 and class 5 as the experimental subjects. And randomly class 4 is selected as experimental class to adopt the model of deep learning with reflection, while class 5 is selected as compared class to adopt the model of deep learning without reflection. 2) Treatment phase Knowledge content is the object for learners to recognize and practice [5]. Spiro considers that knowledge can be divided into well-structured knowledge and ill-structured knowledge, accordingly learning can be called primary learning and advanced leaning. Deep learning aims to solve the ill-structured problem of the real social situation and complex technology environment through the integration of multi-dimensional knowledge and the construction of new knowledge and meaning [6]. So the involved knowledge should be complex, open and ill-structured, and also easy to integrate, construct and contextualize. Reflection-based deep learning intents to discover, inquire and solve problem by the reflection and regulation of learning process and outcome, and then promote the development of high-level thinking and the realization of deep leaning. So we can say that the two key points of reflection-based deep learning are reflection and problemsolving. Hence we choose the chapter "the acquisition and processing of image" from information technology course in senior middle as the teaching content of our experiment. And based on the process model of reflection-based deep learning and the teaching objectives of the experimental section, we design the experimental program and put it into practice [7]. The concrete process of reflection is as following: a) Reflection in the inductive stage Before the new class, we will guide learners to review the old knowledge by creating the problem situationhow to make a poster with texts and pictures. And then elicit the new teaching content by asking the question-how to deal with the pictures. Meanwhile, require learners to fill in "the pre-course self-test form". b) Reflection in the main stage The reflection in class mainly follows the "ConflictReflection-Generation" mode, as shown in Figure 2 when lecturing on "the classification and comparison of graphs and pictures", that is, to create the cognitive conflicts by showing two different kinds of images, and then require learners to generate solution to eliminate them through reflecting old knowledge. Besides, this reflection can also follows the "Variant-Reflection-Migration" mode, as shown in Figure 3, to regulate the process of variant practice through reflection and promote the exploration and solving of new problems, for example when asking learners to design and create their own work by Photoshop. Meanwhile, require them to fill in the record form about work designing and creating, which aims to guide learners to reflect, extract the relevant knowledge and skills, and regulate their work creation. Fig. 2. The Reflection following "Conflict-Reflection-Generation" mode Fig. 3. The Reflection following "Variant-Reflection-Migration" mode c) Reflection in the evaluated stage After every class, learners are required to reflect on their classroom learning process and result by fill in a record form

We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.

We previously showed that vasoactive intestinal peptide (VIP) protects against bacterial pathogen-induced epithelial barrier disruption and colitis, although the mechanisms remain poorly defined. The aim of the current study was to identify cellular pathways of VIP-mediated protection with use of pharmacological inhibitors during enteropathogenic Escherichia coli (EPEC) infection of Caco-2 cell monolayers and during Citrobacter rodentium-induced colitis. EPEC-induced epithelial barrier disruption involved the PKC pathway but was independent of functional cAMP, Rho, and NF-κB pathways. VIP mediated its protective effects by inhibiting EPEC-induced PKC activity and increasing expression of the junctional protein claudin-4. Short-term treatment with TPA, which is known to activate PKC, was inhibited by VIP pretreatment, while PKC degradation via long-term treatment with TPA mimicked the protective actions of VIP. Immunostaining for specific PKC isotypes showed upregulated expression of PKCθ and PKCε during EPEC infection. Treatment with specific inhibitors revealed a critical role for PKCε in EPEC-induced barrier disruption. Furthermore, activation of PKCε and loss of barrier integrity correlated with claudin-4 degradation. In contrast, inhibition of PKCε by VIP pretreatment or the PKCε inhibitor maintained membrane-bound claudin-4 levels, along with barrier function. Finally, in vivo treatment with the PKCε inhibitor protected mice from C. rodentium-induced colitis. In conclusion, EPEC infection increases intracellular PKCε levels, leading to decreased claudin-4 levels and compromising epithelial barrier integrity. VIP inhibits PKCε activation, thereby attenuating EPEC-induced barrier disruption.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder affecting neuromuscular junctions, which is strongly associated with thymoma. Usually, the target of the autoimmune attack is the acetylcholine receptor (AChR) of the postsynaptic skeletal muscle endplate. However, non-AChR

Unexpected reaction pathways have been unravelled that are involved in the generation of 2,2,5,5-substituted tetrahydrofurans from the mesylate of 5-hydroxy-5-methyl-6-oxo-2-phenyl-2-piperidinemethanol (7). Upon treatment of 7 with amines under controlled conditions two reactive intermediates could be isolated. The first is a strained aziridine-fused lactam, 1-azabicyclo[4.1.0]heptan-2-one 10, which reacts further with amines or methoxide at the lactam carbonyl group to form γ-hydroxyalkylaziridines. Final N-acylation results in internal OH attack to give the hydrofuran products. Reaction of 10 with some other nucleophiles led to 3,3,6,6-substituted 2-piperidinones.

Rationale The ischemic penumbra assessment is essential for the subsequent therapy and prediction of evolution in patients with acute ischemic infraction. Although controversial as a perfect equivalence to penumbra, perfusion-weighted imaging (PWI)-diffusion-weighted imaging (DWI) mismatch may predict the response to thrombolysis. Due to the reliance of PWI on contrast agents, noninvasive alternatives remain an unmet need. Patient concerns We reported a 65-year-old man complained of paroxysmal hemiplegia of his right limbs and anepia for 2 days, whereas the symptoms lasted for about 12 hours when he admitted to the hospital. Diagnosis We diagnosed it as acute ischemic stroke caused by the left middle cerebral artery stenosis. Interventions Susceptibility-weighted imaging (SWI), multimodal magnetic resonance imaging (MRI) work-up which includes conventional MRI sequences (T1WI, T2WI, and FLAIR), DWI, PWI. Outcomes His DWI-SWI mismatch was comparable to that of DWI-PWI at admission, suggesting that DWI-SWI could predict ischemic penumbra in patient with acute infarction. He refused the digital subtraction angiography examination or stenting, and he was treated with aspirin, atorvastain, and supportive treatment. The patient received a reexamination of the conventional MRI and SWI 11 days later. Expansion of the infarction in the affected MCA territory resulted from the penumbra indicated by the mismatch between DWI-SWI. Lessons SWI can be used as a noninvasive alternative to evaluate the ischemic penumbra. Besides, SWI can provide perfusion information comparable to PWI and SWI is sufficient to identify occlusive arteries.

To investigate the clinical characteristics and short-term prognosis of elderly patients with Guillain–Barré syndrome (GBS). We retrospectively analyzed the clinical data of adult GBS. According to the age, the enrolled subjects were divided into 2 groups, that is, patients ≥60 years (elderly group) and those aged 18 to 59 years (nonelderly group). The clinical characteristics and short-term prognosis of the patients in the 2 groups were compared. In total, 535 patients were enrolled. There were 67 patients fell into the elderly group with a mean age of 69 years old; while 468 patients fell into the nonelderly group with a mean age of 39 years old. We found that the elderly patients had significantly lower incidence of antecedent infections (49.3% vs 66.2%, P

BACKGROUND Pseudomonas aeruginosa (P. aeruginosa) predominated in hospitals. METHODS In order to determine the source of the outbreak and take effective measures to prevent the spread, we tested their relationships between the strains. 97 P. aeruginosa samples were analyzed by multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA) method. In order to identify a minimal subset that could provide high discrimination, we evaluated the ability of various VNTR sets. RESULTS The result showed all of the 11 loci displayed high discrimination, and the lowest loci was ms223 (h = 0.59). The 97 strains were all discriminated (HGDI = 1.0000). The top 7-locus set produced a HGDI value of 1.0000, which was the same as the 11-locus set. The 4-locus set had a HGDI value of 0.9972 with a clustering rate of 11.3%. The strains were divided into four groups based on the phylogenetic clustering and genotypic characteristics. There were obvious differences among the four groups regarding the drug-resistance patterns of Imipenem, Ciprofloxacin, Ceftazidime, Levofloxacin, Meropenem, Piperacillin, Cefepime, Aztreonam (p < 0.05). CONCLUSIONS In conclusion, the transmission of the strains was not found in this study. The 7-locus set yielded a high discrimination, while for an easier and more robust MLVA scheme, the number of markers can be reduced to 4 loci of ms212, ms211, ms213, and ms142. These four strains from four inpatients in the same ward displayed the same drug resistance spectrum. The MLVA genotype results showed the four strains had the same gene structures. The four patients were from the same treatment group. They showed the IMP-1 allele and belonged to the aac (6')-I type, and there was a deletion of the OprD2 gene in four strains, supporting the MLVA results in suggesting that they are similar.

Background Whole-organ engineering provides a new alternative source of donor organs for xenotransplantation. Utilization of decellularized whole-organ scaffolds, which can be created by detergent perfusion, is a strategy for tissue engineering. In this article, our aim is to scale up the decellularization process to human-sized liver and kidney to generate a decellularized matrix with optimal and stable characteristics on a clinically relevant scale. Methods Whole porcine liver and kidney were decellularized by perfusion using different detergents (1% SDS, 1% Triton X-100, 1% peracetic acid (PAA), and 1% NaDOC) via the portal vein and renal artery of the liver and kidney, respectively. After rinsing with PBS to remove the detergents, the obtained liver and kidney extracellular matrix (ECM) were processed for histology, residual cellular content analysis, and ECM components evaluation to investigate decellularization efficiency, xenoantigens removal, and ECM preservation. Results The resulting liver and kidney scaffolds in the SDS-treated group showed the most efficient clearance of cellular components and xenoantigens, including DNA and protein, and preservation of the extracellular matrix composition. In comparison, cell debris was observed in the other decellularized groups that were generated using Triton X-100, PAA, and NaDOC. Special staining and immunochemistry of the porcine liver and kidney ECMs further confirmed the disrupted three-dimension ultrastructure of the ECM in the Triton X-100 and NaDOC groups. Additionally, Triton X-100 effectively eliminated the residual SDS in the SDS-treated group, which ensured the scaffolds were not cytotoxic to cells. Thus, we have developed an optimal method that can be scaled up for use with other solid whole organs. Conclusions Our SDS-perfusion protocol can be used for porcine liver and kidney decellularization to obtain organ scaffolds cleared of cellular material, xenoimmunogens, and preserved vital ECM components.

Inflammatory Bowel Diseases (IBD), including Crohn's Disease and Ulcerative Colitis, have long been associated with a genetic basis, and more recently host immune responses to microbial and environmental agents. Dinitrobenzene sulfonic acid (DNBS)-induced colitis allows one to study the pathogenesis of IBD associated environmental triggers such as stress and diet, the effects of potential therapies, and the mechanisms underlying intestinal inflammation and mucosal injury. In this paper, we investigated the effects of dietary n-3 and n-6 fatty acids on the colonic mucosal inflammatory response to DNBS-induced colitis in rats. All rats were fed identical diets with the exception of different types of fatty acids [safflower oil (SO), canola oil (CO), or fish oil (FO)] for three weeks prior to exposure to intrarectal DNBS. Control rats given intrarectal ethanol continued gaining weight over the 5 day study, whereas, DNBS-treated rats fed lipid diets all lost weight with FO and CO fed rats demonstrating significant weight loss by 48 hr and rats fed SO by 72 hr. Weight gain resumed after 72 hr post DNBS, and by 5 days post DNBS, the FO group had a higher body weight than SO or CO groups. Colonic sections collected 5 days post DNBS-treatment showed focal ulceration, crypt destruction, goblet cell depletion, and mucosal infiltration of both acute and chronic inflammatory cells that differed in severity among diet groups. The SO fed group showed the most severe damage followed by the CO, and FO fed groups that showed the mildest degree of tissue injury. Similarly, colonic myeloperoxidase (MPO) activity, a marker of neutrophil activity was significantly higher in SO followed by CO fed rats, with FO fed rats having significantly lower MPO activity. These results demonstrate the use of DNBS-induced colitis, as outlined in this protocol, to determine the impact of diet in the pathogenesis of IBD.

Although microembolus monitoring has been widely used for ischemic cerebrovascular disease, the clinical significance of microembolic signal (MES) in asymptomatic middle cerebral artery (MCA) stenosis remains unclear. We aim to investigate the frequency of MES and the value of MES in predicting ischemic stroke secondary to asymptomatic MCA stenosis. From June 2011 to December 2012, microembolus monitoring was performed in 83 asymptomatic and 126 symptomatic subjects. By comparing the demographics and risk factors between the symptomatic and asymptomatic subjects, we found that the ratio of male sexuality and smoking history differed (101/126 vs 43/83, and 88/126 vs 38/83, respectively, p

4-(Hetero)aryl-2-oxa-5-azabicyclo[2.2.2]octan-3-ones and 3,6-diones, formed via cycloaddition of 2H-1,4-oxazin-2-ones and ethene followed by functional group transformation, undergo lactone cleavage by reaction with amines to yield substituted 2-(hetero)aryl-5-hydroxy-2-piperidinecarboxamides. Subsequent reduction affords the corresponding 2-piperidinemethanamines. Both amide and amine compounds are of interest as potential Substance P antagonists. A detailed NMR study, supported by conformational calculations, of an octahydro-2H-pyrido[1,2-a]pyrazine analogue revealed the existence of a temperature and solvent dependent equilibrium mixture of transoid and cisoid invertomers.

1,1,4,4-Tetrasubstituted cyclopenta[c]piperidines and the corresponding 4,4,7,7-pyrrolo[3,4-c]piperidines have been synthesised via cycloaddition of 5-chloro-6-methyl-3-phenyl-2H-1,4-oxazin-2-one with cyclopentene and 3-pyrroline derivatives, respectively, followed by reductive opening of the lactone-bridged adducts. The axial-equatorial conformational preferences of the substituents in these cis-fused bicyclic systems were opposite to those for the monocyclic piperidine analogues. The specific array of functional groups in the bicyclic aminoalcohols was used to accommodate, in stereocontrolled fashion, variable pharmacophoric groups that are of interest for substance P antagonist activity.

2,(2),5,5-Tri- and tetrasubstituted analogues of 5-hydroxy-2-piperidinemethanol and 5-hydroxy-6-oxo-2-piperidinecarboxylic acid have been prepared via Diels–Alder reaction of 3-substituted 2H-1,4-oxazin-2-ones with ethene followed by functional group transformation of the resulting imidoyl chloride and lactone groups. Some of the 2-piperidinemethanol products are converted further into potential substance P antagonists.

Lambert-Eaton myasthenic syndrome (LEMS) is frequently associated with malignancy, especially small cell lung cancer (SCLC). Here, we describe a patient with a 5-year history of cervical myelopathy who presented with recurrent limb weakness of her limbs and complained of recent progressive weakness. Following an examination that included electromyography, a chest CT scan, and a bronchofiberscopy examination with brushing biopsy, the patient was diagnosed with LEMS and SCLC. This case report highlights the ongoing need for clinicians to be observant for cases of LEMS, to consider both patient history and physical examination data, and to accurately obtain a differential diagnosis between LEMS and other diseases, which also cause weakness.

Redox-inactive metal ions play pivotal roles in regulating the reactivities of high-valent metal-oxo species in a variety of enzymatic and chemical reactions. A mononuclear non-heme Mn(IV)-oxo complex bearing a pentadentate N5 ligand has been synthesized and used in the synthesis of a Mn(IV)-oxo complex binding scandium ions. The Mn(IV)-oxo complexes were characterized with various spectroscopic methods. The reactivities of the Mn(IV)-oxo complex are markedly influenced by binding of Sc(3+) ions in oxidation reactions, such as a ~2200-fold increase in the rate of oxidation of thioanisole (i.e., oxygen atom transfer) but a ~180-fold decrease in the rate of C-H bond activation of 1,4-cyclohexadiene (i.e., hydrogen atom transfer). The present results provide the first example of a non-heme Mn(IV)-oxo complex binding redox-inactive metal ions that shows a contrasting effect of the redox-inactive metal ions on the reactivities of metal-oxo species in the oxygen atom transfer and hydrogen atom transfer reactions.

Background:Reversible splenial lesion syndrome (RESLES) is a rare clinico-radiological disorder with unclear pathophysiology. Clinically, RESLES is defined as reversible isolated splenial lesions in the corpus callosum, which can be readily identified by magnetic resonance imaging (MRI) and

Vitamin D deficiency affects more that 1 billion people worldwide and is associated with an increased risk of developing a number of inflammatory/autoimmune diseases, including inflammatory bowel disease (IBD). At present, the basis for the impact of vitamin D on IBD and mucosal immune responses is unclear; however, IBD is known to reflect exaggerated immune responses to luminal bacteria, and vitamin D has been shown to play a role in regulating bacteria-host interactions. Therefore, to test the effect of active vitamin D on host responses to enteric bacteria, we gave 1,25(OH)2D3to mice infected with the bacterial pathogen Citrobacter rodentium, an extracellular microbe that causes acute colitis characterized by a strong Th1/Th17 immune response. 1,25(OH)2D3treatment of infected mice led to increased pathogen burdens and exaggerated tissue pathology. In association with their increased susceptibility, 1,25(OH)2D3-treated mice showed substantially reduced numbers of Th17 T cells within their infected colons, whereas only modest differences were noted in Th1 and Treg numbers. In accordance with the impaired Th17 responses, 1,25(OH)2D3-treated mice showed defects in their production of the antimicrobial peptide REG3γ. Taken together, these studies show that 1,25(OH)2D3suppresses Th17 T-cell responses in vivo and impairs mucosal host defense against an enteric bacterial pathogen.

Schistosomiasis, caused by infection with Schistosoma species, remains an important parasitic zoonosis. Thioredoxin glutathione reductase of Schistosoma japonicum (SjTGR) plays an important role in the development of the parasite and for its survival. Here we present a recombinant plasmid DNA vaccine, pVAX1/SjTGR, to estimate its protection against S. japonicum in BALB/c mice. The DNA vaccine administrated by particle bombardment induced higher protection than by intramuscular injection. All animals vaccinated with pVAX1/SjTGR developed significant specific anti-SjTGR antibodies than control groups. Moreover, animals immunized by gene gun exhibited a splenocyte proliferative response, with an increase in IFN- γ and IL-4. The recombinant plasmid administrated by gene gun achieved a medium protective efficacy of 27.83-38.83% (P < 0.01) of worm reduction and 40.38-44.51% (P < 0.01) of liver egg count reduction. It suggests that different modes of administering a DNA vaccine can influence the protective efficacy induced by the vaccine. Interestingly, from the enzymatic activity results, we found that worms obtained from pVAX1/SjTGR-vaccinated animals expressed lower enzymatic activity than the control group and the antibodies weakened the enzymatic activity of SjTGR in vitro, too. It implies that the high-level antibodies may contribute to the protective effects.

A mononuclear non-heme manganese(IV)-oxo complex has been synthesized and characterized using various spectroscopic methods. The Mn(IV)-oxo complex shows high reactivity in oxidation reactions, such as C-H bond activation, oxidations of olefins, alcohols, sulfides, and aromatic compounds, and N-dealkylation. In C-H bond activation, the Mn(IV)-oxo complex can activate C-H bonds as strong as those in cyclohexane. It is proposed that C-H bond activation by the non-heme Mn(IV)-oxo complex does not occur via an oxygen-rebound mechanism. The electrophilic character of the non-heme Mn(IV)-oxo complex is demonstrated by a large negative ρ value of -4.4 in the oxidation of para-substituted thioanisoles.

The tegument proteins of schistosomes are regarded as potential vaccine candidates and drug targets to control schistosomiasis. Nucleotide pyrophosphatase/phosphodiesterase-5 (NPP-5), which belongs to a multigene family of nucleotide pyrophosphatase/phosphodiesterases (NPPs), is important in the hydrolysis of pyrophosphate or phosphodiester bonds in nucleotides and their derivatives. In the present study, SjNPP-5, identified as one of the tegument proteins of Schistosoma japonicum in our previous proteomic studies, was cloned on a fragment of 1,371 bp and expressed as a recombinant protein of 69 kDa. Real-time RT-PCR analysis showed that SjNPP-5 was up-regulated at 21-42 days, and the expression level in 42-day-old male worms was almost nine times higher than that in females. Western blot analysis revealed that rSjNPP-5 had good antigenicity. Immunofluorescence analysis found that SjNPP-5 was a membrane-associated antigen mainly distributed on the surface of the male adult worm of S. japonicum. BALB/c mice vaccinated with rSjNPP-5 three times showed a 29.90% worm reduction (P 0.05) and a 26.21% egg count reduction (P 0.05). Immunization with rSjNPP-5 induced a mixed Th1/Th2 response in which Th1 was dominant. The response was characterized by a reduced IgG1/IgG2a ratio and elevated production of cytokines IFN-γ and IL-4. This study suggested that SjNPP-5 may be important in schistosome development, and further investigations are required to fully understand the function of this molecule.