A Real-World Study Comparing Various Antimicrobial Regimens for Bloodstream Infections Caused by Carbapenem-Resistant Gram-Negative Bacilli in a Tertiary Hospital, Shanghai, China, from 2010 to 2017.

BACKGROUND: We conducted a real-world analysis of the effectiveness of different antibiotic regimens for bloodstream infections (BSIs) caused by carbapenem-resistant gram-negative bacilli (CR-GNB) in a Chinese population. METHODS: A retrospective observational study was conducted between January 2010 and December 2017. Patients with BSIs caused by CR-GNB confirmed by in vitro susceptibility tests were enrolled, and patient medical record data on antimicrobial agents and microbiological and clinical outcomes were extracted. RESULTS: A total of 175 individuals were included; 127 individuals (72.6%) received combination therapy (two or more antibiotics), while 48 individuals (27.4%) received monotherapy (single antibiotic). The all-cause 28-day mortality was 20.0%. Treatment success or presumed success rates were very similar between the monotherapy and combination therapy groups (58.3% versus 59.1%; P = 0.931). Combination therapy had a higher success rate trend than monotherapy in septic shock patients (40.7% versus 18.2%; P = 0.268). Improved therapeutic effects were observed in the active agent-containing group, although the differences were not significant. CONCLUSION: Combination therapy likely has better therapeutic effects on critical BSIs caused by CR-GNB than monotherapy. Choosing a proper active agent in an antimicrobial regime is relatively crucial to the ultimate treatment outcome.

miR-378a-3p inhibits ischemia/reperfusion-induced apoptosis in H9C2 cardiomyocytes by targeting TRIM55 via the DUSP1-JNK1/2 signaling pathway.

MicroRNAs (miRNAs) are involved in many pathological and biological processes, such as ischemia/reperfusion (I/R) injury by modulating gene expression. Increasing evidence indicates that miR-378a-3p might provide a potential cardioprotective effect against ischemic heart disease. Cell apoptosis is a crucial mechanism in I/R injury. As such, this study evaluated the protective effects and underlying mechanisms of action of miR-378a-3p on H9C2 cardiomyocyte apoptosis following I/R injury. We found that I/R-induced H9C2 cardiomyocytes exhibited a decrease in miR-378a-3p expression, while treatment with a miR-378a-3p mimic suppressed cell apoptosis, JNK1/2 activation, cleavage of PARP and caspase-3, and Bax/Bcl-2 ratio but increased DUSP1 expression, which subsequently inhibited JNK1/2 phosphorylation. TRIM55 was shown to be a target of miR-378a-3p and its downregulation inhibited the miR-378a-3p inhibitor-induced increase in cell apoptosis and JNK1/2 activation. TRIM55 inhibited DUSP1 protein expression through ubiquitination of DUSP1. Moreover, DUSP1 overexpression inhibited the TRIM55 overexpression-induced increase in cell apoptosis and JNK1/2 activation. The protective effect of miR-378a-3p was subsequently confirmed in a rat myocardial I/R model, as evidenced by a decrease in cardiomyocyte apoptosis of cardiomyocytes, TRIM55 expression, and JNK1/2 activation. Taken together, these results suggest that miR-378a-3p may protect against I/R-induced cardiomyocyte apoptosis via TRIM55/DUSP1/JNK signaling.

FAM46C inhibits lipopolysaccharides-induced myocardial dysfunction via downregulating cellular adhesion molecules and inhibiting apoptosis.

AIMS: Sepsis is a syndrome of inflammatory response induced by infection. Cellular adhesion molecules may involve in sepsis-induced myocardial dysfunction (SIMD) which is a major predictor of morbidity and mortality of sepsis. Here we studied the role of FAM46C in AC16 cells and c57 mice with lipopolysaccharides (LPS) treatment. MAIN METHODS: Real-time PCR and western blot were used to detect the expression level of relative genes and protein. Cell proliferation and apoptosis were evaluated. KEY FINDINGS: Interestingly, negative correlation between Toll-like receptor 4 (TLR4) and FAM46C in sepsis was observed. The overexpression of FAM46C reduced the apoptosis induced by LPS in AC16 cells. Inhibition of apoptosis contributed by FAM46C was mediated by adhesion molecule via blocking p38 and ERK/MAPK signaling pathway. Moreover, overexpression of Fam46c and inhibition of TLR4 by TAK-242 could attenuate apoptosis induced by LPS in vivo. SIGNIFICANCE: FAM46C played an important role in SIMD via inhibiting LPS-induced myocardial dysfunction by downregulating cellular adhesion molecules and inhibiting apoptosis. It was the first time to explore the role of FAM46C in SIMD in this study.

Bacterial Distribution and Risk Factors of Nosocomial Blood Stream Infection in Neurologic Patients in the Intensive Care Unit.

OBJECTIVE: To investigate the risk factors and analyze the distribution of pathogens to provide a basis for the prevention of nosocomial blood stream infections (BSI) and reduce the incidence and mortality of nosocomial BSI in neurologic patients. PATIENTS AND METHODS: A retrospective chart review of neurologic patients admitted to an adult intensive care unit from January 2012 to December 2017 was conducted. Every positive blood culture, clinical demographic, microbiologic and laboratory result, as well as 28-day outcome data, were compiled on a data collection sheet. The clinical significance of each isolate was determined; in addition, the antimicrobial susceptibilities of causative pathogens and the most likely source were recorded. RESULTS: During the five-year study period, there were 121 nosocomial BSI yielding 151 isolates in 404 neurologic patients. Eighty-one percent of nosocomial BSI were monomicrobial. Gram-positive organisms caused 67.9% of these BSI, gram-negative organisms caused 32.1%, and fungi caused 0.8%. The crude incidence rate was approximately 29.9%, and the mortality of nosocomial BSI was as high as 29.8%. Intravascular lines were the most common source of nosocomial BSI (79.3%). The most common organisms causing BSI were coagulase-negative staphylococci (CoNS; 44.6% of isolates), Staphylococcus aureus (17.4%), Klebsiella species (11.5%), and Acinetobacter spp. (11.5%). Multivariable regression analysis revealed that the use of antibiotic agents in the 90 days prior (odds ratio [OR], 5.81; 95% confidence interval [CI], 3.18-10.62; p = 0.001), brain trauma (OR, 0.28; 95% CI, 0.15-0.51; p = 0.001), and transfusion (OR, 3.02; 95% CI, 1.45-6.29; p = 0.001) were significant predictors of nosocomial BSI. CONCLUSIONS: The incidence and mortality of nosocomial BSI were high in our neurologic patients. Strictly aseptic operations, hand hygiene, and reasonable use of transfusions and antibiotic agents are effective measures to prevent nosocomial BSI.

A suppurative thyroiditis and perineal subcutaneous abscess related with aspergillus fumigatus: a case report and literature review.

BACKGROUND: Invasive aspergillosis is a complication in immunocompromised patients and commonly detected in patients with hematological malignancies, which mostly affect the lungs. Because of its high iodine content, rich blood supply and capsule, the thyroid is considered to be less prone to microbial invasion thus most infectious thyroiditis cases are caused by bacteria. However, a few case reports have described thyroid gland aspergilloses, most of which were due to disseminated invasive aspergillosis. CASE PRESENTATION: We first report a case of thyroid gland and subcutaneous labium majus aspergillosis in a Chinese patient who received long-term glucocorticoid treatment for systemic lupus erythematosus (SLE) and lupus nephritis, and then we reviewed 36 articles describing similar aspergillus infections in 41 patients. CONCLUSION: We included 29 cases of diagnosed aspergillus thyroiditis and analyzed clinical findings, treatments and outcomes to provide clinical information for diagnosis and prognosis of thyroiditis caused by Aspergillus fumigatus.

Glycyrrhizin affects monocyte migration and apoptosis by blocking HMGB1 signaling.

Monocytes serve an important role in systemic inflammation. High mobility group box­1 protein (HMGB1) promotes recruitment and suppresses apoptosis in monocytes through the receptor for advanced glycation end products/ nuclear factor (NF)­κB and toll­like receptor 4/mitogen­activated protein kinase (MAPK)/extracellular signal­regulated kinase (ERK) signaling pathways. Glycyrrhizin (GL), an effective component of licorice, weakens the proinflammatory effect of HMGB1. The present study investigated the effect of GL on the migration and apoptosis of monocytes associated with HMGB1 signaling. THP­1 cells were used to evaluate the behavior of monocytes in response to GL treatment, and the downstream pathways were investigated. GL suppressed HMGB1­induced monocyte migration and increased HMGB1­inhibited monocyte apoptosis. GL inhibited the activation of the NF­κB and MAPK/ERK signaling pathways induced by HMGB1 and decreased the expression of monocyte chemoattractant protein­1 (MCP­1) and myeloid cell leukemia 1 (Mcl­1). Taken together, the results indicated that GL may suppress the migration of monocytes and induce apoptosis to reduce systemic inflammation by blocking downstream NF­κB/MCP­1 and MAPK/ERK/Mcl­1 signaling pathways.

Glycyrrhizin Protects Rats from Sepsis by Blocking HMGB1 Signaling.

Background. HMGB1 acts as an important inflammatory mediator and is a potential therapeutic target for sepsis. Glycyrrhizin (GL), a natural triterpene glycoside derived from licorice, has been demonstrated to inhibit HMGB1 activity. The aim of this study is to explore how GL affects the HMGB1 signaling in sepsis. Methods. We used a CLP model of sepsis and in vitro LPS or HMGB1-treated NR8383 cells to examine the effects of GL on expression of HMGB1 and proinflammatory cytokines. Furthermore, we explored the effect of GL on interactions between HMGB1 and RAGE or TLR4 and the activations of NF-κB and MAPKs. Results. GL significantly decreased mortality and reduced serum levels of HMGB1 in vivo. GL also attenuated the release and expression of HMGB1 and proinflammatory cytokines. Direct stimulation by HMGB1 elevated the release of proinflammatory cytokines faster than LPS did and it was also inhibited by GL. Furthermore, GL blocked the interaction of HMGB1 with RAGE and TLR4 and suppressed the downstream MAPKs/NF-κB signaling pathway. Conclusion. GL may protect rats against sepsis by blocking the interaction of HMGB1 with cell surface receptors and HMGB1-mediated inflammatory responses.

Expression of c-FLIP in a rat model of sepsis and its effects on endothelial apoptosis.

Sepsis is characterized by the impaired regulation of inflammatory responses. Apoptosis is important in the pathogenesis of sepsis. Cellular FLICE­inhibitory protein (c­FLIP) is a catalytically inactive caspase­8 homologue, which negatively interferes with apoptotic signaling. The role of c­FLIP in sepsis and in endothelial cell apoptosis, a critical step in the pathogenesis of sepsis, remains controversial. In the present study, to investigate the relationship between c­FLIP and sepsis, a rat model of sepsis was induced by cecal ligation and puncture, and western blot analysis was used to detect the expression of c­FLIPL, the long isoform of c­FLIP. Lower protein expression levels of c­FLIPL were found in the brain, intestine and lung of the rat sepsis model, compared with the rats in the sham surgery group. The association between the expression of c­FLIPL and endothelial cell apoptosis was further examined in vitro by c­FLIPL overexpression and flow cytometry, which demonstrated that the expression of c­FLIPL was inversely correlated with endothelial cell apoptosis. These data suggested that c­FLIP may be important in sepsis and shed light on therapeutic strategies.

Moisture chamber versus lubrication for corneal protection in critically ill patients: a meta-analysis.

PURPOSE: Critically ill patients in the intensive care unit are at increased risk of exposure keratopathy. There is limited evidence available to make the best choice of eye care modality. This meta-analysis aimed to evaluate the effect of moisture chamber compared with lubrication for corneal protection in critically ill patients. METHODS: Studies were identified through PubMed, Embase, The Cochrane Library, and complementary manual searches, up to May 31, 2014. Randomized controlled trials of critically ill patients in the intensive care unit comparing moisture chamber with lubrication and evaluating risk of corneal damage were included. RESULTS: Seven trials were included. The pooled analysis showed that the use of moisture chambers resulted in a reduction of the incidence of corneal damage [risk ratio (RR), 0.27; 95% confidence interval (CI): 0.11-0.67; P = 0.005]. In 1 subgroup analysis, there was a significant difference between the use of moisture chambers and lubricating drops, and the moisture chamber group had a decreased incidence of corneal damage (RR, 0.13; 95% CI: 0.05-0.35; P < 0.0001). In the other subgroup analysis, no statistically significant difference was observed between the use of moisture chambers and lubricating ointments (RR, 0.81; 95% CI: 0.51-1.29; P = 0.38). The overall quality of evidence was low. CONCLUSIONS: The use of moisture chambers is associated with more effective corneal protection compared with lubrication. The analytic result is limited by serious risk of bias and imprecision.

Procalcitonin as a marker of sepsis and outcome in patients with neurotrauma: an observation study.

BACKGROUND: Procalcitonin (PCT) is a reliable biomarker of sepsis and infection. The level of PCT associated with sepsis and infection in patients with traumatic brain injury is currently unknown. The purpose of this study was to investigate the value of PCT and C-reactive protein (CRP) as diagnostic markers of sepsis and to evaluate the prognostic value of these markers related to the severity of injury, sepsis and mortality. METHODS: 105 adult patients with neurotrauma were enrolled in this study from June 2011 to February 2013. PCT and CRP were measured at admission and 2, 3, 5 and 7 days after admission. The sepsis criteria established by American College of Chest Physicians /Society of Critical Care Medicine Consensus Conference were used to identify patients. Injury Severity Score (ISS) and Glasgow Coma Score (GCS) were used to assess the severity of the injury. All these patients were monitored for 28 days. RESULTS: At admission, the median level of PCT was consistent with the severity of brain injury as follows: mild 0.08 ng/ml (0.05 - 0.13), moderate 0.25 ng/ml (0.11 - 0.55) and severe 0.31 ng/ml (0.17 - 0.79), but the range of CRP levels varied greatly within the given severity of brain injury. Seventy-one (67.6%) patients developed sepsis. The initial levels of PCT at admission were statistically higher in patients with sepsis, compared with patients with systemic inflammatory response syndrome (SIRS), but there were no differences in the initial concentration of CRP between sepsis and SIRS. After adjusting for these parameters, multivariate logistic regression analysis revealed that PCT was an independent risk factor for septic complications (p < 0.05). The areas under the ROCs at admission for the prediction of mortality were 0.76 (p < 0.05) and 0.733 for PCT and CRP, respectively. CONCLUSIONS: Increased levels of PCT during the course of the ICU stay could be an important indicator for the early diagnosis of sepsis after neurotrauma. In addition, high serum levels of PCT in patients with neurotrauma at admission indicate an increased risk of septic complications, and the daily measurement of PCT assists in guiding antibiotic therapy in neurotrauma patients.

Effects of Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) pretreatment on septic rats.

To evaluate the effects of Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) injection on the survival rate of rats post cecal ligation and puncture (CLP), Sprague-Dawley (SD) rats were subcutaneously injected with 0.125 ml, 0.25 ml or 0.5 ml PA-MSHA for 8 days or 16 days before CLP. The survival rate and physiological appearance of rats in each group were monitored daily post CLP. The expression of Toll-like receptor 4 (TLR4) and cytokines related to inflammation was evaluated. We found that the 0.5 ml-8d (0.5 ml PA-MSHA injected for 8 days) group had the highest 7-day survival rate (91.7%), which was significantly improved compared with the CLP-only group (33.3%). Furthermore, our results showed that PA-MSHA effectively increased serum pro-inflammatory mediators (TNF-α, IL-1ß and IL-6) at the early stage (8 days) but increased anti-inflammatory mediators (IL-4 and IL-10) at the late stage (16 days). PA-MSHA significantly up-regulated the mRNA expression of TLR4 at 8 and 16 days. After PA-MSHA pretreatment, CLP had no marked effect on the levels of most inflammatory factors. To explore potential protective mechanisms of PA-MSHA against CLP, we examined the effect of PA-MSHA on murine macrophage-like RAW264.7 cells and found that PA-MSHA induced endotoxin tolerance. In conclusion, this study suggested that precisely controlling the dosage and time of PA-MSHA administration can effectively increase the rat survival rate post CLP, which may be mediated through regulating inflammatory mediators and inducing endotoxin tolerance.

Glycyrrhizin protects against porcine endotoxemia through modulation of systemic inflammatory response.

INTRODUCTION: Glycyrrhizin (GL) was recently found to suppress high-mobility group box 1 (HMGB1)-induced injury by binding directly to it. However, the effect of GL on HMGB1 expression in endotoxemia as well as its underlying molecular mechanism remained unclear. METHODS: Twenty-one pigs were divided into four groups: sham group (n=3), control group (n=6), ethyl pyruvate group (n=6) and glycyrrhizin group (n=6). Pigs were anesthetized, mechanically ventilated, monitored and given a continuous intravenous infusion of lipopolysaccharide (LPS). Twelve hours after the start of the LPS infusion, ethyl pyruvate (30 mg/kg/hr) or glycyrrhizin (1 mg/kg/hr) was administered for 12 hours. Systemic and pulmonary hemodynamics, oxygen exchange, and metabolic status were measured. The concentrations of cytokines in serum and the corresponding gene and protein expressions in tissue samples from liver, lungs, kidneys, small intestine and lymph nodes were measured. RESULTS: GL maintained the stability of systemic hemodynamics and improved pulmonary oxygen exchange and metabolic status. GL also attenuated organ injury and decreased the serum levels of HMGB1 and other pro-inflammatory cytokines by inhibiting their gene and protein expression. CONCLUSIONS: GL improved systemic hemodynamics and protected vital organs against porcine endotoxemia through modulation of the systemic inflammatory response. By reducing the serum level and gene expression of HMGB1 and other pro-inflammatory cytokines, GL may become a potential agent for the treatment of sepsis.

Overexpression of high mobility group box 1 and 2 is associated with the progression and angiogenesis of human bladder carcinoma.

High mobility group box 1 (HMGB1) and HMGB2 overexpression has been observed in several human tumor types, and is involved in cancer progression and prognosis. However, the clinicopathological significance of HMGB1 and HMGB2 expression in bladder carcinoma (BCa), particularly the involvement of these proteins in angiogenesis, remains unclear. In the present study, immunohistochemistry and real-time polymerase chain reaction (PCR) of HMGB1 and HMGB2 in 64 BCa patients revealed that HMGB1 and HMGB2 were overexpressed in BCa tissues compared with normal tissues, and were correlated with tumor clinical stage and pathological grade. In addition, correlation analysis of vascular endothelial growth factor (VEGF) and microvessel density (MVD) counts indicated that the overexpression of HMGB1 and HMGB2 was also correlated with angiogenesis. We conclude that HMGB proteins act as key regulators in the progression and angiogenesis of bladder carcinoma, and serve as potential diagnostic and therapeutic targets.

Molecular mechanism of sustained inflation in acute respiratory distress syndrome.

BACKGROUND: The aim of this study was to investigate the effect and the potential molecular mechanism of sustained inflation (SI) recruitment maneuvers in acute respiratory distress syndrome (ARDS) in beagle dog following endotracheal suctioning. METHODS: ARDS was induced in 24 beagle dogs with oleic acid. They had mechanical ventilation support. They were randomized into four groups after the establishment of the ARDS model: non-SI-open group where no SI was applied in beagle dogs with ARDS following open endotracheal suctioning; non-SI-closed group where no SI was applied in beagle dogs with ARDS following closed endotracheal suctioning; SI-open group where SI was applied in beagle dogs with ARDS following open endotracheal suctioning; and SI-closed group where SI was applied in beagle dogs with ARDS following closed endotracheal suctioning. Oxygenation, indexes of respiratory mechanics, and hemodynamic indexes were serially measured during the procedure. The serum protein level, or the messenger RNA in the heart and lung, of inflammation-related cytokines was investigated. RESULTS: SI in ARDS improved oxygenation, lung compliance, and airway resistance but had no significant effect in the hemodynamic indexes. At molecular level, SI in ARDS neutralized the increases of pro-inflammatory cytokines (tumor necrosis factor α, interleukin 1ß [IL-1ß], and IL-6), and anti-inflammatory cytokine (IL-10) in the serum. Furthermore, SI in ARDS increased aquaporin 1 and aquaporin 5 messenger RNA in the lung tissue, and decreased IL-6 messenger RNA in the lung and heart tissue. CONCLUSION: SI in ARDS could improve oxygenation, lung compliance, and airway resistance, which was related to the improved degree of inflammation and better maintained aquaporins.

The relationship between serum levels of uric acid and prognosis of infection in critically ill patients.

BACKGROUND: Serum uric acid level is associated with some chronic diseases and prognosis of severe infection. This study aimed to investigate the relationship between serum uric acid (SUA) and prognosis of infection in critically ill patients. METHODS: The data from 471 patients with infection admitted from January 2003 to April 2010 were analyzed retrospectively at Huashan Hospital Affiliated to Fudan University, Shanghai, China. The data of SUA, serum creatinine, blood urea nitrogen (BUN) and other relevant examinations within 24 hours after admission were recorded and the levels of SUA in those patients were described, then Student's t test was used to evaluate the relationship between SUA and pre-existing disorders. Different levels of SUA were graded for further analysis. The Chi-square test was used to examine the difference in the prognosis of infection. RESULTS: The mean initial level of SUA within 24 hours after admission was 0.232±0.131 mmol/L and the median was 0.199 mmol/L. Remarkable variations in the initial levels of SUA were observed in patients with pre-existing hypertension (t=-3.084, P=0.002), diabetes mellitus (t=-2.487, P=0.013), cerebral infarction (t=-3.061, P=0.002), renal insufficiency (t=-4.547, P<0.001), central nervous system infection (t=5.096, P<0.001) and trauma (t=2.875, P=0.004). SUA was linearly correlated with serum creatinine and BUN (F=159.470 and 165.059, respectively, P<0.001). No statistical correlation was found between the initial levels of SUA and prognosis of infection (χ2=60.892, P=0.100). CONCLUSION: The current study found no direct correlation between the initial levels of SUA after admission and prognosis of infection in critically ill patients.