Epigallocatechin-3-gallate Synergistically Enhanced Arecoline-Induced Cytotoxicity by Redirecting Cycle Arrest to Apoptosis.

Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can reduce ROS levels and potentially prevent cancer progression but may paradoxically enhance the survival of cancer cells. This study investigated whether epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, could resolve this paradox. Prostate cancer cells (PC-3 cell line) were cultured and treated with arecoline combined with NAC (N-acetylcysteine) or EGCG; the combined effects on intracellular ROS levels and cell viability were examined using the MTT and DCFDA assays, respectively. In addition, apoptosis, cell cycle, and protein expression were investigated using flow cytometry and western blot analysis. Our results showed that EGCG, similar to NAC (N-acetylcysteine), reduced the intracellular ROS levels, which were elevated by arecoline. Moreover, EGCG not only caused cell cycle arrest but also facilitated cell apoptosis in arecoline-treated cells in a synergistic manner. These were evidenced by elevated levels of cyclin B1 and p27, and increased fragmentation of procaspase-3, PARP, and DNA. Our findings highlight the potential use of EGCG for cancer prevention and therapy.

Staphylococcal phosphatidylinositol-specific phospholipase C potentiates lung injury via complement sensitisation.

Staphylococcus aureus is frequently isolated from patients with community-acquired pneumonia and acute respiratory distress syndrome (ARDS). ARDS is associated with staphylococcal phosphatidylinositol-specific phospholipase C (PI-PLC); however, the role of PI-PLC in the pathogenesis and progression of ARDS remains unknown. Here, we showed that recombinant staphylococcal PI-PLC possesses enzyme activity that causes shedding of glycosylphosphatidylinositol-anchored CD55 and CD59 from human umbilical vein endothelial cell surfaces and triggers cell lysis via complement activity. Intranasal infection with PI-PLC-positive S. aureus resulted in greater neutrophil infiltration and increased pulmonary oedema compared with a plc-isogenic mutant. Although indistinguishable proinflammatory genes were induced, the wild-type strain activated higher levels of C5a in lung tissue accompanied by elevated albumin instillation and increased lactate dehydrogenase release in bronchoalveolar lavage fluid compared with the plc- mutant. Following treatment with cobra venom factor to deplete complement, the wild-type strain with PI-PLC showed a reduced ability to trigger pulmonary permeability and tissue damage. PI-PLC-positive S. aureus induced the formation of membrane attack complex, mainly on type II pneumocytes, and reduced the level of CD55/CD59, indicating the importance of complement regulation in pulmonary injury. In conclusion, S. aureus PI-PLC sensitised tissue to complement activation leading to more severe tissue damage, increased pulmonary oedema, and ARDS progression.

Carbon Monoxide Inhibits Receptor Activator of NF-κB (RANKL)-Induced Osteoclastogenesis.

BACKGROUND: Low concentrations of carbon monoxide (CO) have anti-inflammatory effects and can reduce bone erosion in a murine collagen-induced arthritis model. The objective of this study was to assess the effects of CO on receptor activator of NF-κB ligand (RANKL), one of the key stimulators of osteoclastogenesis. METHODS: The in vivo effects of CO on RANKL expression were assessed in a collagen antibody-induced arthritis model in mice. Cell proliferation and apoptosis were assessed in the RAW246.7 cell line stimulated with RANKL and exposed to either air or CO. The number of tartrate resistant acid phosphatase (TRAP)-positive RAW246.7 cells was also examined after treatment with RANKL and the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, Troglitazone. RESULTS: CO reduced RANKL expression in the synovium of arthritic mice. Although CO slightly increased RAW246.7 cell proliferation, no differences in activated caspase 3 levels were detected. In addition, Troglitazone ameliorated the inhibitory effects of CO on RANKL-induced TRAP expression by RAW246.7 cells. CONCLUSIONS: CO suppresses osteoclast differentiation by inhibiting the RANKL-induced activation of PPAR-γ. Given the role of the PPAR-γ/cFos (AP-1) pathway in regulating the transcription factor, NFATc1, the master regulator of osteoclastogenesis, further studies are warranted to explore CO in treating inflammatory bone disorders.

The significant association of CCND1 genotypes with colorectal cancer in Taiwan.

Colorectal cancer, one million cases of diagnosis worldwide annually, is one of the most common malignant tumors and 20 % incidence caused by low penetrance susceptibility genes. Cyclin D1 (CCND1) regulating cell cycle transition may determine the susceptible individuals to genomic instability and carcinogenesis. The study aimed at examining the contribution of CCND1 genotypes to colorectal cancer risk in Taiwan. The genotypes of CCND1 A870G (rs9344) and G1722C (rs678653) were determined among 362 colorectal cancer patients and 362 age- and gender-matched cancer-free controls. Significant differences were observed between colorectal cancer and control groups in the distributions of genotypic (P = 9.71 × 10(-4)) and allelic (P = 0.0017) frequencies at CCND1 A870G. Additionally, individuals carried AG or GG genotype had 0.56- or 0.51-fold higher of odds ratios for developing colorectal cancer than the AA genotype (95 % confidence intervals = 0.40-0.78 and 0.32-0.81, respectively). Furthermore, G allele of CCND1 A870G performed a protective effects for nonsmokers and nonalcohol drinkers (P = 0.0012 and 0.0007, respectively) on colorectal cancer risk. These findings support the concept that the cell cycle regulation may play a role in colorectal cancer initiation and development and CCND1 A870G genotyping maybe a feasible technology for colorectal cancer early detection.

Analysis of dermal papilla cell interactome using STRING database to profile the ex vivo hair growth inhibition effect of a vinca alkaloid drug, colchicine.

Dermal papillae (DPs) control the formation of hair shafts. In clinical settings, colchicine (CLC) induces patients' hair shedding. Compared to the control, the ex vivo hair fiber elongation of organ cultured vibrissa hair follicles (HFs) declined significantly after seven days of CLC treatment. The cultured DP cells (DPCs) were used as the experimental model to study the influence of CLC on the protein dynamics of DPs. CLC could alter the morphology and down-regulate the expression of alkaline phosphatase (ALP), the marker of DPC activity, and induce IκBα phosphorylation of DPCs. The proteomic results showed that CLC modulated the expression patterns (fold>2) of 24 identified proteins, seven down-regulated and 17 up-regulated. Most of these proteins were presumably associated with protein turnover, metabolism, structure and signal transduction. Protein-protein interactions (PPI) among these proteins, established by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, revealed that they participate in protein metabolic process, translation, and energy production. Furthermore, ubiquitin C (UbC) was predicted to be the controlling hub, suggesting the involvement of ubiquitin-proteasome system in modulating the pathogenic effect of CLC on DPC.

Intratumoral decorin gene delivery by AAV vector inhibits brain glioblastomas and prolongs survival of animals by inducing cell differentiation.

Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of nude mice through an adeno-associated viral (AAV2) gene delivery system. Decorin expression from the AAV vector in vitro inhibited cultured U87MG cell growth by induction of cell differentiation. Intracranial injection of AAV-decorin vector to the glioma-bearing nude mice in vivo significantly suppressed brain tumor growth and prolonged survival when compared to control non-treated mice bearing the same U87MG tumors. Proteomics analysis on protein expression profiles in the U87MG glioma cells after AAV-mediated decorin gene transfer revealed up- and down-regulation of important proteins. Differentially expressed proteins between control and AAV-decorin-transduced cells were identified through MALDI-TOF MS and database mining. We found that a number of important proteins that are involved in apoptosis, transcription, chemotherapy resistance, mitosis, and fatty acid metabolism have been altered as a result of decorin overexpression. These findings offer valuable insight into the mechanisms of the anti-glioblastoma effects of decorin. In addition, AAV-mediated decorin gene delivery warrants further investigation as a potential therapeutic approach for brain tumors.

The joint effect of hOGG1 genotype and smoking habit on endometriosis in Taiwan.

This study has two aims: [1] to evaluate the association between hOGG1 genotypic polymorphism and endometriosis risk, and [2] to investigate the joint effects of hOGG1 genotype and smoking habit on endometriosis susceptibility in Taiwan. For this purpose, the well-known polymorphic variants of hOGG1, codon 326, was genotyped and analyzed of its association with the risk of endometriosis. In total, 153 patients with endometriosis and 636 non-endometriosis healthy controls were recruited and genotyped. The methodology for genotyping is polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Pearson's Chi-square test was performed to compare the distributions of the genotypes between case and control groups. The results showed that the hOGG1 codon 326 genotypes were not differently distributed between the endometriosis and non-endometriosis control groups in both genotypic (P = 0.6212) and allelic (P = 0.4006) frequency analysis. We have further analyzed the genotypic-smoking joint effects on endometriosis risk and found an obvious interaction between hOGG1 codon 326 genotypes and smoking status. The hOGG1 codon 326 genotypes were increased in endometriosis risk only in the smoker groups (P = 0.0061), but not in the non-chewer group (P = 0.0648). Our results provide the evidence that the hOGG1 codon 326 genotype may have a joint effect with smoking on the development of endometriosis.

A Proteomics-Based Identification of the Biological Networks Mediating the Impact of Epigallocatechin-3-Gallate on Trophoblast Cell Migration and Invasion, with Potential Implications for Maternal and Fetal Health.

Trophoblast migration and invasion play crucial roles in placental development. However, the effects of (-)-epigallocatechin-3-gallate (EGCG) on trophoblast cell functions remain largely unexplored. In this study, we investigated the impact of EGCG on the survival of trophoblast cells and employed a proteomics analysis to evaluate its influence on trophoblast cell migration and invasion. Be-Wo trophoblast cells were treated with EGCG, and a zone closure assay was conducted to assess the cell migration and invasion. Subsequently, a proteomics analysis was performed on the treated and control groups, followed by a bioinformatics analysis to evaluate the affected biological pathways and protein networks. A quantitative real-time PCR and Western blot analysis were carried out to validate the proteomics findings. Our results showed that EGCG significantly suppressed the trophoblast migration and invasion at a concentration not affecting cell survival. The proteomics analysis revealed notable differences in the protein expression between the EGCG-treated and control groups. Specifically, EGCG downregulated the signaling pathways related to EIF2, mTOR, and estrogen response, as well as the processes associated with the cytoskeleton, extracellular matrix, and protein translation. Conversely, EGCG upregulated the pathways linked to lipid degradation and oxidative metabolism. The quantitative PCR showed that EGCG modulated protein expression by regulating gene transcription, and the Western blot analysis confirmed its impact on cytoskeleton and extracellular matrix reorganization. These findings suggest EGCG may inhibit trophoblast migration and invasion through multiple signaling pathways, highlighting the potential risks associated with consuming EGCG-containing products during pregnancy. Future research should investigate the impact of EGCG intake on maternal and fetal proteoforms.

The total synthesis of a ganglioside Hp-s1 analogue possessing neuritogenic activity by chemoselective activation glycosylation.

The total synthesis of ganglioside 2, an analogue of the ganglioside Hp-s1 (1) which displays neuritogenic activity toward the rat pheochromocytoma cell line PC-12 cell in the presence of nerve growth factor (NGF) with an effect (34.0%) greater than that of the mammalian ganglioside GM 1 (25.4%), was accomplished by applying a chemoselective-activation glycosylation strategy. Moreover, we also demonstrate that the synthesized ganglioside 2 exhibited neuritogenic activity toward the human neuroblastoma cell line SH-SY5Y without the presence of NGF.

Erythrocyte degradation, metabolism, secretion, and communication with immune cells in the blood during sepsis: A review.

Sepsis is a health issue that affects millions of people worldwide. It was assumed that erythrocytes were affected by sepsis. However, in recent years, a number of studies have shown that erythrocytes affect sepsis as well. When a pathogen invades the human body, it infects the blood and organs, causing infection and sepsis-related symptoms. Pathogens change the internal environment, increasing the levels of reactive oxygen species, influencing erythrocyte morphology, and causing erythrocyte death, i.e., eryptosis. Characteristics of eryptosis include cell shrinkage, membrane blebbing, and surface exposure of phosphatidylserine (PS). Eryptotic erythrocytes increase immune cell proliferation, and through PS, attract macrophages that remove the infected erythrocytes. Erythrocyte-degraded hemoglobin derivatives and heme deteriorate infection; however, they could also be metabolized to a series of derivatives. The result that erythrocytes play an anti-infection role during sepsis provides new perspectives for treatment. This review focuses on erythrocytes during pathogenic infection and sepsis.

Innovative Hybrid-Alignment Annotation Method for Bioinformatics Identification and Functional Verification of a Novel Nitric Oxide Synthase in Trichomonas vaginalis.

Both the annotation and identification of genes in pathogenic parasites are still challenging. Although, as a survival factor, nitric oxide (NO) has been proven to be synthesized in Trichomonas vaginalis (TV), nitric oxide synthase (NOS) has not yet been annotated in the TV genome. We developed a witness-to-suspect strategy to identify incorrectly annotated genes in TV via the Smith-Waterman and Needleman-Wunsch algorithms through in-depth and repeated alignment of whole coding sequences of TV against thousands of sequences of known proteins from other organisms. A novel NOS of TV (TV NOS), which was annotated as hydrogenase in the NCBI database, was successfully identified; this TV NOS had a high witness-to-suspect ratio and contained all the NOS cofactor-binding motifs (NADPH, tetrahydrobiopterin (BH4), heme and flavin adenine dinucleotide (FAD) motifs). To confirm this identification, we performed in silico modeling of the protein structure and cofactor docking, cloned the gene, expressed and purified the protein, performed mass spectrometry analysis, and ultimately performed an assay to measure enzymatic activity. Our data showed that although the predicted structure of the TV NOS protein was not similar to the structure of NOSs of other species, all cofactor-binding motifs could interact with their ligands with high affinities. We clearly showed that the purified protein had high enzymatic activity for generating NO in vitro. This study provides an innovative approach to identify incorrectly annotated genes in TV and highlights a novel NOS that might serve as a virulence factor of TV.

Rab23 plays a role in the pathophysiology of mesangial cells--a proteomic analysis.

Rab23, a novel member of the Rab family of small GTPases, has recently been identified in mesangial cells (MCs). Although Rab23 levels in MCs are associated with glomerular nephropathies, the exact physiological and pathological roles of Rab23 in MCs are unknown. In the present study, its roles in MCs were explored by performing proteomics and systems biology analyses in MCs after knockdown or overexpression of Rab23. Knockdown of Rab23 was achieved by transfecting MCs with a plasmid expressing short hairpin RNA against Rab23, while overexpression of Rab23 was accomplished by transfection with the wild-type, dominant negative, and constitutively active Rab23 gene constructs. The effects of different levels of Rab23 activity on proteome of various biological pathways were investigated. Gel-based proteomic approaches and systems biology tools, respectively, were used to identify the Rab23-regulated proteins and the functional pathways. Proteomic analysis revealed the potential roles for Rab23 in multiple processes, including G-protein signal transduction, transcription modulation, RNA stabilization, protein synthesis and degradation, cytoskeleton reorganization, anti-oxidation and detoxification, circadian rhythm regulation and phagocytosis. Bioinformatics analyses showed that Rab23 impacts on multiple biological networks in MCs. These data may shed light on the roles of Rab23 in mesangiopathy or MC damage.

Endovascular aortic repair is a cost-effective option for in-hospital patients with abdominal aortic aneurysm.

BACKGROUND: To investigate the cost-effectiveness of endovascular aortic repair (EVAR) versus open aortic repair (OAR) for abdominal aortic aneurysm (AAA) using incremental costs per decreased in-hospital mortality rate gained through our patients' cohort. METHODS: Medical records and healthcare costs of patients with AAA hospitalized between 2010 and 2015 were extracted from the National Health Insurance Research Database (NHIRD) of Taiwan. Multiple regression analysis was applied to adjust for confounding factors and to compare the differences in postoperative clinical outcomes between patients who received EVAR and OAR. The incremental cost-effectiveness ratio (ICER) of EVAR was determined based on the healthcare cost obtained from the analyzed data. RESULTS: A total of 2803 AAA patients were identified (n = 559 with ruptured AAA and n = 2244 unruptured AAA). Patients with ruptured AAA who underwent EVAR compared with OAR patients had shorter hospital and intensive care unit (ICU) stays (all p < 0.05). For patients with unruptured AAA, those who received EVAR compared with OAR, the adjusted odds ratio (aOR) of postoperative complications and in-hospital mortality were 0.371 and 0.447 (all p < 0.05). The total direct surgical costs and medical expenses during hospitalization in all AAA patients were higher for the EVAR group; however, ICER was <1 per capita gross domestic product. Stratification by age groups further suggested that ICER for patients with unruptured AAA who received EVAR, compared with OAR, decreased with age. CONCLUSION: Total direct medical costs were higher for AAA patients receiving EVAR regardless of rupture status; however, the cost is offset by lower odds of postoperative complications and in-hospital mortality. The observed decrease in ICER with age and EVAR use warrants further analysis. Our findings further validate the use of EVAR over OAR. These results provides supporting evidence for physicians and patients with AAA to inform shared decision making regarding endovascular or OAR options.

Early Screening of Risk for Multidrug-Resistant Organisms in the Emergency Department in Patients With Pneumonia and Early Septic Shock: Single-Center, Retrospective Cohort Study.

OBJECTIVES: Pneumonia is the fourth leading cause of death globally, with rapid progression during sepsis. Multidrug-resistant organisms (MDROs) are becoming more common with some healthcare-associated pneumonia events. Early detection of MDRO risk improves the outcomes; however, MDROs risk in pneumonia with sepsis is unknown. This study investigated the disease outcomes of pneumonia with septic shock in patients admitted in the emergency department (ED) intensive care unit (ICU), a population with a high prevalence of MDROs, after early screening of MDROs risk. METHODS: In this retrospective cohort study, patients with pneumonia and early septic shock (n = 533) admitted to the ED at the Taipei Tzu Chi Hospital from 2013 to 2019 were selected. The study population was divided into four subgroups after the MDROs risk and screening procedure were completed within 1 or 6 h of admission. ICU mortality and multidrug antibiotic therapy were compared. RESULTS: The high-risk MDROs groups had higher percentage of P aeruginosa than the low-risk group. Furthermore, the appropriate ED first antibiotics were higher in the 1-h subgroup than in the 6-h subgroup of the high-risk MDROs group. In multivariate analysis, the 6-h high-risk MDROs group had an adjusted odds ratio of 7.191 (95% CI: 2.911-17.767, P < 0.001) and 2.917 (95% CI: 1.456-5.847, P = 0.003) for ICU mortality and multidrug therapy in the ICU, respectively, after adjusting for other confounding factors. CONCLUSIONS: MDRO screening within 1 h is recommended following admission of patients with pneumonia and early septic shock in the ED, especially in areas with a high prevalence of MDROs.

Isoelectric focusing management: an investigation for salt interference and an algorithm for optimization.

Two-dimensional electrophoresis (2-DE) has evolved into a robust separation technique in proteomic research. However, one of the major challenges in 2-DE experiments, the reproducibility of the first dimensional electrophoresis (IEF), has remained unsolved. It is well-known that the quality of IEF experiments is significantly affected by the salt interference. Nevertheless, the interference mechanisms of salts in IEF have never been systematically investigated. In this study, we comprehensively investigated the interference effects in IEF due to various kinds of simple and buffer salts in protein samples. Two interference schemes were proposed accordingly to elucidate the interference mechanisms of salts in IEF. Furthermore, to increase the reproducibility of IEF, we proposed that conductivity measurement is a feasible method to assess the salt content of 2-DE samples and developed an algorithm to predict the optimal total volt-hours (Vh) required for protein focusing in IEF. The developed algorithm had been evaluated under various IEF conditions for a variety of 2-DE samples and proven to be a reliable guide. In sum, information disclosed in this study should be of use for increasing the reproducibility and thus the applicability of 2-DE in current proteomics.

Neurotrophic effects of tianeptine on hippocampal neurons: a proteomic approach.

Tianeptine, an atypical tricyclic antidepressant with unique characteristics, can improve memory and prevent stress-induced hippocampal damage. It has neuroplastic and neurotrophic effects on hippocampal neurons and can prevent dendritic atrophy of the hippocampus in certain pathological conditions. To obtain a better understanding of the underlying mechanisms, we performed a proteomic analysis on tianeptine-treated hippocampal neurons. Primary hippocampal neurons were prepared from fetal Sprague-Dawley rats, eliminating glia cells by addition of cytosine beta-D-arabinofuranoside at day 2 in vitro (DIV2). The neurons were treated with tianeptine (10 microg/mL) or vehicle at DIV3, then harvested at DIV4 or DIV9 for immunocytochemical analysis of, respectively, neurite outgrowth or synapse formation. A proteomics analysis was performed on DIV4 neurons and the data were confirmed by Western blot analysis. Using specific markers, we demonstrated that tianeptine can augment neurite growth and promote synaptic contacts in cultured hippocampal neurons. The proteomics analysis identified 11 differentially expressed proteins, with roles in neurite growth, metabolism of neurotrophic substances, synaptogenesis, and synaptic activity homeostasis. The data shed light on the mechanisms underlying the neurotrophic effect of tianeptine observed in both animal studies and the clinic.

A proteomics-based translational approach reveals an antifolate resistance inherent in human plasma derived from blood donation.

The inhibition of dihydrofolate reductase (DHFR) by antifolates is a common practice both in cell culture and in chemotherapy. Surprisingly, antifolate resistance was also observed in cultured murine myeloma cells (SP2/0) in the presence of human plasma (HP); thus, we used a proteomic approach to identify novel plasma biomarker(s) for this condition. In contrast to the in vitro antifolate response, metabolic enzymes and translation machinery proteins were found to be up-regulated in the presence of HP. The antifolate resistance inherent in HP may be explained by a simultaneous promotion of cell proliferation and the maintenance of DNA integrity. Furthermore, the factor(s) was found to be extrinsic, heat stable and very small in size. Adenine, a supplemented additive in erythrocyte preservation, was subsequently identified as the contributing factor and exogenous addition in cultures reversed the cytotoxicity induced by antifolates. Importantly, adenine-containing blood components, which may provide enhanced survival to otherwise sensitive antifolate-targeted cells, showed a dose-dependent adverse effect in transfusion recipients receiving antifolate (methotrexate) medications. These findings not only highlight a previously unnoticed role of adenine, but also emphasize a novel mechanistic link between transfusion and subsequently reduced survival in patients taking methotrexate.

In vivo evidence of duality effects for lovastatin in a nude mouse cancer model.

Statins, hydroxy-methyl-glutaryl coenzyme A reductase inhibitors, are the most effective medication for lowering cholesterol, cardiovascular morbidity and mortality. On the basis of our previous in vitro experimental results on an anaplastic thyroid cancer cell line, we designed a nude mouse model in which cancer cells were seeded subcutaneously to examine the potential anticancer effects of lovastatin in vivo. As expected, tumor growth was significantly reduced in the mice treated with 5 or 10 mg/kg/day of lovastatin compared with the positive control group. However, the tumor grew much faster in the mice treated with 1 mg/kg/day of lovastatin than in the positive control group. We suspect this result might be related to vascular endothelial growth factor. In this model, we found that lovastatin inhibits tumor growth at a high dosage (5 or 10 mg/kg/day), suggesting it could be used as an effectively adjuvant chemotherapy for cancer. However, it also promotes tumor growth at a low dosage (1 mg/kg/day). This duality effect should be further studied for patients treated with various dosages of statins.

Tianeptine reduces morphine antinociceptive tolerance and physical dependence.

Long-term use of morphine can cause neuronal dystrophic changes in specific areas of the brain. These changes may underlie the mechanism for developing morphine antinociceptive tolerance and physical dependence. We evaluated the effect of tianeptine, an antidepressant with prominent neuroprotective and neuroplastic properties, on the development of morphine antinociceptive tolerance and physical dependence. Male C57BL/6 mice were rendered tolerant to or dependent on morphine by subcutaneously injecting them with morphine (10 mg/kg) and intraperitoneally with saline or tianeptine (1, 3, or 5 mg/kg) twice daily for 6 days. The mice were given a daily tail-flick test 1 h after the first morphine injection to evaluate the development of their tolerance to morphine antinociception. To evaluate their physical dependence on morphine, 3 h after the final morphine injection on day 6, naloxone-HCl-precipitated (2 mg/kg, intraperitoneally) withdrawal symptoms were counted for 30 min, and body weight was checked 1 h after the naloxone injection. Tianeptine per se produced no antinociception, neither did it modify the antinociception produced by morphine, nor did it evoke the behavioral responses different from those in the saline controls. The combination of tianeptine with morphine significantly reduced the development of morphine antinociceptive tolerance and suppressed the incidence of naloxone-precipitated withdrawal symptoms. We conclude that tianeptine is an effective inhibitor of morphine-induced antinociceptive tolerance and physical dependence in mice. Our results would imply that comedication with tianeptine and morphine might benefit those who need long-term morphine treatment.

Ignorance of pre-ED healthcare setting is a factor leading to inappropriate initial antibiotic treatment of sepsis in ED and poor outcomes in ICU.

OBJECTIVES: Appropriate initial antibiotic therapy is critical for successfully treating sepsis. In the emergency department (ED), clinicians often rely on septic symptoms to guide empirical therapy. The aim of this study was to investigate whether history of contacting pre-ED healthcare setting is easy to be neglected and whether the patients received more inappropriate initial antibiotic therapy and developed poorer outcomes. METHODS: Septic patients (n = 453) admitted from ED to the intensive care unit (ICU) between 2014 and 2017 were retrospectively selected. Appropriate antibiotic treatment or not was determined by checking whether the selected antibiotics can effectively eradicate the bacteria identified. Various indexes were compared between patients with appropriate and inappropriate initial antibiotic treatments, including septic symptoms (qSOFA scores) in ED, septic-severity change in ICU (SOFA-score ratios), and septic outcomes (APACHE II scores, stay length, 30-day survival probability). These indexes were also compared between pre-ED healthcare and pre-ED community patients. RESULTS: In comparison with pre-ED community patients, pre-ED healthcare patients received more inappropriate initial antibiotic treatment in ED, showing poorer outcomes in ICU, including septic severity, stay-lengths in ICU and 30-day survival probabilities. Pre-ED settings is more significant than qSOFA scores to predict the inappropriate initial antibiotic treatment. CONCLUSIONS: Pre-ED healthcare settings, which are indexes for infection with antibiotic resistant pathogens, are easy to be neglected in the first hour in ED. We suggested that standard operating procedure for getting enough information of pre-ED settings should be incorporated to the 1 h bundle of sepsis guideline.