Mechanistic and biophysical characterization of polymyxin resistance response regulator PmrA in Acinetobacter baumannii.

Introduction: Acinetobacter baumannii PmrAB is a crucial two-component regulatory system (TCS) that plays a vital role in conferring resistance to polymyxin. PmrA, a response regulator belonging to the OmpR/PhoB family, is composed of a C-terminal DNA-binding effector domain and an N-terminal receiver domain. The receiver domain can be phosphorylated by PmrB, a transmembrane sensor histidine kinase that interacts with PmrA. Once phosphorylated, PmrA undergoes a conformational change, resulting in the formation of a symmetric dimer in the receiver domain. This conformational change facilitates the recognition of promoter DNA by the DNA-binding domain of PmrA, leading to the activation of adaptive responses. Methods: X-ray crystallography was carried out to solve the structure of PmrA receiver domain. Electrophoretic mobility shift assay and Isothermal titration calorimetry were recruited to validate the interaction between the recombinant PmrA protein and target DNA. Field-emission scanning electron microscopy (FE-SEM) was employed to characterize the surface morphology of A. baumannii in both the PmrA knockout and mutation strains. Results: The receiver domain of PmrA follows the canonical α5ß5 response regulator assembly, which undergoes dimerization upon phosphorylation and activation. Beryllium trifluoride is utilized as an aspartate phosphorylation mimic in this process. Mutations involved in phosphorylation and dimerization significantly affected the expression of downstream pmrC and naxD genes. This impact resulted in an enhanced cell surface smoothness with fewer modifications, ultimately contributing to a decrease in colistin (polymyxin E) and polymyxin B resistance. Additionally, a conservative direct-repeat DNA PmrA binding sequence TTTAAGNNNNNTTTAAG was identified at the promoter region of the pmrC and naxD gene. These findings provide structural insights into the PmrA receiver domain and reveal the mechanism of polymyxin resistance, suggesting that PmrA could be a potential drug target to reverse polymyxin resistance in Acinetobacter baumannii.

A regimen based on the combination of trimethoprim/sulfamethoxazole with caspofungin and corticosteroids as a first-line therapy for patients with severe non-HIV-related pneumocystis jirovecii pneumonia: a retrospective study in a tertiary hospital.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening and severe disease in immunocompromised hosts. A synergistic regimen based on the combination of sulfamethoxazole-trimethoprim (SMX-TMP) with caspofungin and glucocorticosteroids (GCSs) may be a potential first-line therapy for PJP. Therefore, it is important to explore the efficacy and safety of this synergistic therapy for treating non-HIV-related PJP patients. METHODS: We retrospectively analysed the data of 38 patients with non-HIV-related PJP at the First Affiliated Hospital of Xi'an Jiaotong University. Patients were divided into two groups: the synergistic therapy group (ST group, n = 20) and the monotherapy group (MT group, n = 18). All patients were from the ICU and were diagnosed with severe PJP. In the ST group, all patients were treated with SMX-TMP (TMP 15-20 mg/kg per day) combined with caspofungin (70 mg as the loading dose and 50 mg/day as the maintenance dose) and a GCS (methylprednisolone 40-80 mg/day). Patients in the MT group were treated only with SMX-TMP (TMP 15-20 mg/kg per day). The clinical response, adverse events and mortality were compared between the two groups. RESULTS: The percentage of patients with a positive clinical response in the ST group was significantly greater than that in the MT group (100.00% vs. 66.70%, P = 0.005). The incidence of adverse events in the MT group was greater than that in the ST group (50.00% vs. 15.00%, P = 0.022). Furthermore, the dose of TMP and duration of fever in the ST group were markedly lower than those in the MT group (15.71 mg/kg/day vs. 18.35 mg/kg/day (P = 0.001) and 7.00 days vs. 11.50 days (P = 0.029), respectively). However, there were no significant differences in all-cause mortality or duration of hospital stay between the MT group and the ST group. CONCLUSIONS: Compared with SMZ/TMP monotherapy, synergistic therapy (SMZ-TMP combined with caspofungin and a GCS) for the treatment of non-HIV-related PJP can increase the clinical response rate, decrease the incidence of adverse events and shorten the duration of fever. These results indicate that synergistic therapy is effective and safe for treating severe non-HIV-related PJP.

Management of massive airway hemorrhage associated with extracorporeal membrane oxygenation: A retrospective case series study.

Background and Aims: Extracorporeal membrane oxygenation (ECMO) is an important means of treating patients with respiratory failure. Massive airway hemorrhage is a rare complication of ECMO, with high mortality. The aim of this study was to provide a reference for improving the success rate of treatment of this complication by analyzing and summarizing patient clinical data. Methods: We searched PubMed, Medline, and EMBASE databases for case reports of massive airway bleeding associated with ECMO from January 2000 to January 2022 and included one case treated at our facility. All patients were disconnected from the ventilator, and the endotracheal tube was clamped during treatment, resulting in complete airway packing for hemostasis. The clinical data of these patients were analyzed. Results: Through searching and further screening, two works of literature reported four cases that met our inclusion criteria. Including our patient's case, five patients were included in this study (four adults and one neonate). The longest ECMO treatment time before bleeding was 14 days, and the shortest was 20 min. In all patients, conservative treatment was ineffective after a major airway hemorrhage. They were disconnected from the ventilator and the tracheal tube was clamped for 13-72 h. The four adult patients underwent bronchial artery embolization in the interventional radiology suite. All patients' bleeding stopped after treatment; they were successfully weaned off ECMO and discharged. Conclusions: Treatment measures to disconnect the ventilator and clamp the endotracheal tube with full support from ECMO are feasible for massive airway bleeding associated with ECMO. Early bronchial arteriography and embolization can prevent rebleeding.

Massive Airway Hemorrhage in Severe COVID-19 and the Role of Endotracheal Tube Clamping.

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) has been widely used in treating patients with coronavirus disease 2019 (COVID-19) with severe respiratory failure. However, there are few reports of the successful treatment of patients with massive airway hemorrhage in severe COVID-19 during VV-ECMO treatment. Methods: We analyzed the treatment process of a patient with a massive airway hemorrhage in severe COVID-19, who underwent prolonged VV-ECMO treatment. Results: A 59-year-old female patient was admitted to the intensive care unit after being confirmed to have severe acute respiratory syndrome coronavirus 2 infection with severe acute respiratory distress syndrome. VV-ECMO, mechanical ventilation, and prone ventilation were administered. Major airway hemorrhage occurred on day 14 of ECMO treatment; conventional management was ineffective. We provided complete VV-ECMO support, discontinued anticoagulation, disconnected the ventilator, clipped the tracheal intubation, and intervened to embolize the descending bronchial arteries. After the airway hemorrhage stopped, we administered cryotherapy under bronchoscopy, low-dose urokinase locally, and bronchoalveolar lavage in the airway to clear the blood clots. The patient's condition gradually improved; she underwent ECMO weaning and decannulation after 88 days of VV-ECMO treatment, and the membrane oxygenator was changed out four times. She was successfully discharged after 182 days in hospital. Conclusion: Massive airway hemorrhage in patients with severe COVID-19 and treated with ECMO is catastrophic. It is feasible to clamp the tracheal tube with the full support of ECMO. Notably, bronchoscopy with cryotherapy is effective for removing blood clots.

The assessment in patients with acute fatty liver of pregnancy (AFLP) treated with plasma exchange: a cohort study of 298 patients.

BACKGROUND: To assess the prevalence, risk factors, clinical characteristics of Acute fatty liver of pregnancy (AFLP) patients, and outcomes of AFLP patients treated with plasma exchange (PE). METHODS: We retrospectively reviewed the AFLP patients admitted to the First Affiliated Hospital of Xi'an Jiaotong University and Xijing Hospital of Air Force Medical University from January 2012 to May 2022. Final prediction model for death among AFLP by means of stepwise backward elimination with p value < 0.05. Patients treated with and without PE were compared by propensity-matched cohort study. RESULTS: Two hundred ninety eight patients with the diagnosis of AFLP, and finally 290 patients were enrolled in the cohort study, 50 of whom (17.2%) were dead. Compared with AFLP patients alive, the dead of patients were more likely to be combined encephalopathy (p < 0.01), postpartum hemorrhage (p < 0.01), and found significantly higher frequency of fetal distress (p = 0.04), fetal death (p < 0.01). we developed a predicted probability value and with an area under the receiver operating characteristics (ROC) curve of 0.94 (95%CI 0.87 to 1.00), indicating AFLP patients' death. The patients treated with PE had a significantly lower 60-day mortality rate (OR 0.42, 95% CI 0.29 to 2.64, p = 0.04), and significantly shorter duration of hospital-free days at day 28 (p = 0.01). CONCLUSIONS: In conclusion, our study indicated that liver function were risk factors for maternal mortality, and PE was a protective factor for maternal 60-day mortality and hospital-free days at day 28 in AFLP patients.

Analysis of the extracorporeal anticoagulation effect of modified citrate infusion during continuous renal replacement therapy in critically ill patients.

INTRODUCTION: To analyze the anticoagulation effect of different local infusion methods of citrate underwent continuous renal replacement therapy (CRRT) in critically ill patients. METHODS: The study adopted a single-centre retrospective design. Critically ill patients were divided into conventional group and modified group based on the infusion methods of citrate. RESULTS: The modified group had a longer mean treatment time (67.67 ± 18.69 hours vs. 52.11 ± 24.26 hours, p = 0.007), a lower transmembrane pressure (147.77 ± 66.85 cm H2 O vs. 200.63 ± 118.66 cm H2 O, p = 0.038), fewer citrate bag replacements (1.43 ± 0.50 times vs. 10.60 ± 3.19 times, p < 0.001), and more steady ionized calcium at the venous end (0.35 ± 0.06 mmol/L vs. 0.40 ± 0.05 mmol/L, p = 0.006) compared to the conventional group patients, with statistically significant differences. The incidences of citrate accumulation and tubing coagulation were marginally lower in the modified group. CONCLUSION: The modified local citrate infusion method can prolong treatment time, while reducing both the nursing workload and the occurrence of citrate accumulation.

Progress in structural and functional study of the bacterial phenylacetic acid catabolic pathway, its role in pathogenicity and antibiotic resistance.

Phenylacetic acid (PAA) is a central intermediate metabolite involved in bacterial degradation of aromatic components. The bacterial PAA pathway mainly contains 12 enzymes and a transcriptional regulator, which are involved in biofilm formation and antimicrobial activity. They are present in approximately 16% of the sequenced bacterial genome. In this review, we have summarized the PAA distribution in microbes, recent structural and functional study progress of the enzyme families of the bacterial PAA pathway, and their role in bacterial pathogenicity and antibiotic resistance. The enzymes of the bacterial PAA pathway have shown potential as an antimicrobial drug target for biotechnological applications in metabolic engineering.

MiR-501-5p alleviates cardiac dysfunction in septic patients through targeting NR4A3 to prevent its binding with Bcl-2.

Sepsis-induced myocardial dysfunction is a common complication in septic patients. To date, a limited number of biomarkers that could predict cardiomyocyte apoptosis have been explored. In this study, we successfully established a cecal ligation and puncture (CLP)-induced septic model, and it was found that miR-501-5p expression was down-regulated in peripheral blood samples of septic patients with cardiac dysfunction, lipopolysaccharide (LPS)-induced cardiomyocytes, and the myocardium and peripheral blood in the septic model. Moreover, it was revealed that miR-501-5p overexpression could increase left ventricular diastolic pressure (LVDP), fractional shortening (FS), ejection fraction (EF), and maximum rate of the rise of left ventricular pressure (+dp/dt) in vivo, while it decreased the levels of myocardial injury-related indicators. In addition, LPS induction accelerated apoptosis and elevated the inflammation in HL-1 and HCM cells, which could be reversed by miR-501-5p overexpression. Mechanistically, we considered nuclear receptor subfamily 4 group A member 3 (NR4A3) as the target of miR-501-5p, and it was found that miR-501-5p prevented the binding between NR4A3 and Bcl-2. It was found that miR-501-5p exerted an inhibitory effect on cardiomyocyte apoptosis and inflammation in a NR4A3-dependent manner. Overall, our results may provide evidence for consideration of miR-501-5p in the therapy of sepsis.

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial.

BACKGROUND: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. METHODS: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. RESULTS: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups. CONCLUSIONS: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. TRIAL REGISTRATION: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.

Effectiveness of the improved B-ultrasound method for measuring the antral section to guide enteral nutrition in patients with sepsis in a randomized controlled trial.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate the application of the improved B-ultrasound method (hereafter referred to as B method) for measuring the antral section to evaluate gastric motility in guiding EN for patients with sepsis. METHODS AND STUDY DESIGN: In this single-center, non-blinded, randomized controlled trial, 64 patients with sepsis were randomly enrolled from January 2018 to December 2019. The improved B method (study group) and physicians' clinical experience (control group) were used to guide EN. The two groups patients were separated randomly both. RESULTS: Compared with the control group, the study group had a significantly shorter EN start time, faster initial rate of EN, lower incidence of EN interruption, and shorter Tmax (p<0.05,95% confidence intervals.) and exhibited lower incidences of adverse reactions (p<0.05). Kaplan-Meier survival analysis demonstrated that the study group exhibited significantly fewer adverse EN complications (p=0.029), shorter MV duration, and decreased ICU stay and in-hospital mortality (p<0.05). CONCLUSIONS: The improved B method could perform real-time monitoring of gastric function. Additionally, compared with the physician's personal clinical experience, the improved B method exhibits a better effect in guiding EN for patients with sepsis.

Mild therapeutic hypothermia improves neurological outcomes in a rat model of cardiac arrest.

Cardiac arrest (CA) is the leading cause of death in humans. Research has shown that mild therapeutic hypothermia (MTH) can reduce neurological sequelae and mortality after CA. Nevertheless, the mechanism remains unclear. This study aimed to determine whether MTH promotes neurogenesis, attenuates neuronal damage, and inhibits apoptosis of neurons in rats after CA. Sprague-Dawley rats were divided into the normothermia and mild hypothermia groups. The rats in the normothermia and hypothermia groups were exposed to 2 h of normothermia (36-37℃) and hypothermia (32-33℃), respectively, immediately after resuscitation from 5 min of asphyxial CA. Corresponding control groups not subjected to CA were included. On days 1-6, 5-bromodeoxyuridine (BrdU) 100 mg/kg/day was administered intraperitoneally. The animals were euthanized 1 week after CA. Compared with the normothermia group, the hypothermia group showed a significant increase in the number of doublecortin (DCX) immune-positive cells in the subgranular zone of the hippocampus 1 week after CA. Neurogenesis was assessed using double immunofluorescent labeling of BrdU with neuronal-specific nuclear protein (NeuN)/DCX. There was no marked change in the number of newborn mature (BrdU+-NeuN+) neurons, though there was a significant increase in the number of newborn immature (BrdU+-DCX+) neurons in the hypothermia than in the normothermia group 1 week after CA. Neuronal injury and apoptosis in the CA1 region of the hippocampus, assessed using NeuN immunofluorescence and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays, were significantly reduced in the hypothermia group 1 week after CA. Moreover, mild hypothermia increased the expression of cold-shock protein RNA-binding motif protein 3 (RBM3) in the early stage (24 h/48 h) after CA. These results suggested that mild hypothermia promotes generation of neuronal cells, reduces neuronal injury, and inhibits apoptosis of neurons, which may be related to RBM3 expression.

Acute pancreatitis associated with hemorrhagic fever with renal syndrome: a cohort study of 346 patients.

BACKGROUND: To assess the prevalence, risk factors, clinical characteristics, and outcomes of acute pancreatitis (AP) in patients with hemorrhagic fever with renal syndrome (HFRS). METHODS: All patients diagnosed with HFRS admitted to the First Affiliated Hospital of Xi'an Jiaotong University from January 2013 to July 2020 were enrolled. Patients with and without AP were compared by two risk stratification models: (1) a multivariate regression analysis using propensity score to adjust for confounding and (2) a propensity-matched nested case-control study. RESULTS: A total of 346 patients were enrolled in the cohort study, 29 of whom (8.4%) were diagnosed as AP. There was no significant difference between patients with and without AP with regards to common risk factors and presenting signs/symptoms other than gastrointestinal symptoms (p < 0.01). The patients with AP had a significantly higher 90-day mortality rate (24.1% vs. 3.5%, OR 8.9, 95% CI 1.3 to 103.4, p = 0.045), and significantly shorter duration of therapy free-days to 28 day such as RRT and mechanical ventilation free days (p < 0.05, respectively). CONCLUSIONS: Our study indicated that AP was independently associated with higher mortality in HFRS patients. While considering the difficulty of early recognition of AP among HFRS patients with similar signs and/or symptoms, further laboratory and imaging studies might help identify these patients at risk of poor clinical prognosis.

Comparison of the Protective Effect of Different Mild Therapeutic Hypothermia Temperatures on Intestinal Injury After Cardiopulmonary Resuscitation in Rats.

BACKGROUND: Therapeutic temperature management (TTM) is the standard treatment protocol for unconscious post-resuscitation patients. However, there is still controversy about the ideal targeted temperature of mild hypothermia therapy. Additionally, studies about protective therapy for post-resuscitation intestinal injury are very limited. Therefore, this study was performed to explore: whether mild hypothermia therapy can exert a protective effect on post-resuscitation intestinal injury; the protective effect of different targeted temperatures on post-resuscitation intestinal injury and the ideal targeted temperature; the potential protective mechanism of mild hypothermia therapy for post-resuscitation intestinal injury. METHODS: Ventricular fibrillation was electrically induced and untreated for 6 min while defibrillation was attempted after 8 min of cardiopulmonary resuscitation in 15 rats. After successful resuscitation, animals were randomized into three groups: control; TTM-35; TTM-33. In animals of the control group, temperature was maintained at 37 ±â€Š0.2°C for 6 h. In animals of the two TTM groups, temperature was maintained at 33 ±â€Š0.2°C or 35 ±â€Š0.2°C for 6 h, respectively. During mild hypothermia therapy, intestinal microcirculation was measured at 60, 240, and 360 min after resuscitation. Animals were euthanized 6.5 h after resuscitation. The morphological changes in the intestinal tissue, systemic and local inflammatory factors, and intestinal injury markers were measured and analyzed. The tight junction proteins in the intestinal epithelium, cell-cell contact protein E-cadherin expression, myosin light chain (MLC) and myosin light chain kinase levels, and the NF-κB p65 signaling pathway were analyzed by western blotting. RESULTS: Compared with results in the control group, mild hypothermia therapy (TTM-33 and TTM-35 groups) significantly improved post-resuscitation intestinal microcirculation and pathological scores, decreased systemic and local intestinal tissue inflammatory factor levels, inhibited the NF-κB signaling pathway and downstream MLC phosphorylation, and significantly decreased MLC phosphorylation-associated loss of intestinal tight junction proteins and E-cadherin (P < 0.05). A 33°C target temperature could exert more protective effects than 35°C on post-resuscitation intestinal injury, such as improving intestinal microcirculation, decreasing intestinal ischemia factor iFABP, and plasma endotoxin levels, inhibiting the NF-κB signaling pathway and downstream MLC phosphorylation, and suppressing the loss of intestinal tight junctions and E-cadherin (P < 0.05). CONCLUSIONS: Mild hypothermia therapy can improve post-resuscitation intestinal injury, and a targeted temperature of 33°C may confer more benefit for mitigation of intestinal injury as compared with a targeted temperature of 35°C.

Prognostic value of the combined variability of mean platelet volume and neutrophil percentage for short-term clinical outcomes of sepsis patients.

INTRODUCTION: In this single center retrospective cohort study, 784 patients with sepsis were enrolled and followed up for at least 30 days. The selected endpoint was an all-cause mortality event. METHOD: The relationship between MPV-CV + NEU%-CV and all-cause mortality (in-hospital and 30-day) was analyzed by categorizing the patients into four groups according to MPV-CV and NEU%-CV values. For in-hospital mortality, a significantly higher risk of mortality was observed in patients with an MPV-CV ≥ 15.00% + NEU%-CV ≥ 16.00% than in patients of the other groups (P < 0.001). After adjustment for age, sex, body mass index (BMI), infection site, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, use of vasoactive drugs, mechanical ventilation and renal replacement therapy (RRT), hematocrit, albumin, procalcitonin (PCT), and lactate, logistic regression analysis revealed that an MPV-CV ≥ 15.00% + NEU%-CV ≥ 16.00% was an independent predictive factor for in-hospital mortality [adjusted model: odds ratio (OR) = 4.48, 95% CI = 2.92-6.88, P = 0.001]. RESULTS: After adjustment for age, sex, BMI, infection site, APACHE II score, SOFA score, hematocrit, albumin, PCT, lactate, and the use of vasoactive drugs, mechanical ventilation, and RRT, Cox proportional-hazards regression model revealed that an MPV-CV ≥ 15.00% + NEU%-CV ≥ 16.00% was an independent predictive factor for 30-day mortality [adjusted model 1: hazard ratio (HR) = 7.69, 95% CI = 4.15-14.24, P < 0.001; adjusted model 2: HR = 4.07, 95% CI = 2.50-6.62, P < 0.001]. CONCLUSION: The combination of MPV-CV and NEU%-CV provides a good prognostic value and is a strong independent predictor of short-term clinical outcomes in patients with sepsis. An MPV-CV ≥ 15.00% + NEU%-CV ≥ 16.00% is significantly associated with adverse short-term clinical outcomes.Trial registration number is XJTU2AF2016LSY-04, the registration date is December 2018.

PDLIM2 protects articular chondrocytes from lipopolysaccharide-induced apoptosis, degeneration and inflammatory injury through down-regulation of nuclear factor (NF)-κB signaling.

Excessive inflammatory response-induced apoptosis and the degeneration of articular chondrocytes contribute to the development and progression of osteoarthritis. PDZ and LIM domain containing protein 2 (PDLIM2) has emerged as one of the pivotal regulators in orchestrating an inflammatory response through regulating the activity of transcription factor nuclear factor (NF)-κB. However, whether PDLIM2 participates in the articular chondrocyte-associated inflammatory response in osteoarthritis remains unknown. In the current study, we aimed to explore the biological function of PDLIM2 in lipopolysaccharide (LPS)-stimulated articular chondrocytes, an in vitro model of osteoarthritis. Herein, we found that PDLIM2 expression was significantly down-regulated in chondrocytes in response to LPS exposure. Functional experiments revealed that PDLIM2 overexpression increased the viability and decreased the apoptosis of chondrocytes following LPS treatment. Moreover, PDLIM2 overexpression attenuated LPS-induced degeneration of chondrocytes via the down-regulation of matrix metalloproteinase (MMP)-3 and MMP-13 and the up-regulation of COL2A1 and ACAN. In addition, the overexpression of PDLIM2 decreased LPS-induced production of interleukin (IL)-1ß, IL-6 and TNF-α. In contrast, depletion of PDLIM2 exhibited the opposite effect. Mechanism research elucidated that PDLIM2 repressed the activation of NF-κB signaling associated with the down-regulation of NF-κB p65 protein expression. PDLIM2 depletion-exacerbated LPS-induced injury was significantly reversed by NF-κB inhibition. Taken together, these results demonstrate that PDLIM2 overexpression attenuates LPS-induced injury of articular chondrocytes through the inactivation of NF-κB signaling.

Voriconazole therapeutic drug monitoring in critically ill patients improves efficacy and safety of antifungal therapy.

Since voriconazole plasma trough concentration (VPC) is related to its efficacy and adverse events, therapeutic drug monitoring (TDM) is recommended to perform. However, there is no report about the data of voriconazole TDM in critically ill patients in China. This retrospective study was performed to determine whether voriconazole TDM was associated with treatment response and/or voriconazole adverse events in critically ill patients, and to identify the potential risk factors associated with VPC. A total of 216 critically ill patients were included. Patients were divided into two groups: those underwent voriconazole TDM (TDM group, n = 125) or did not undergo TDM (non-TDM group, n = 91). The clinical response and adverse events were recorded and compared. Furthermore, in TDM group, multivariate logistic regression analysis was performed to identify the possible risk factors resulting in the variability in initial VPC. The complete response in the TDM group was significantly higher than that in the non-TDM group (P = .012). The incidence of adverse events strongly associated with voriconazole in the non-TDM group was significantly higher than that in the TDM group (19.8% vs 9.6%; P = .033). The factors, including age (OR 0.934, 95% CI: 0.906-0.964), male (OR 5.929, 95% CI: 1.524-23.062), serum albumin level (OR 1.122, 95% CI: 1.020-1.234), diarrhoea (OR 4.953, 95% CI: 1.495-16.411) and non-intravenous administration (OR 4.763, 95% CI: 1.576-14.39), exerted the greatest effects on subtherapeutic VPC (VPC < 1.5 mg/L) in multivariate analysis. Intravenous administration (OR 7.657, 95% CI: 1.957-29.968) was a significant predictor of supratherapeutic VPC (VPC > 4.0 mg/L). TDM can result in a favourable clinical efficacy and a lower incidence of adverse events strongly associated with voriconazole in critically ill patients. Subtherapeutic VPC was closely related to younger age, male, hyperalbuminaemia, diarrhoea and non-intravenous administration, and intravenous administration was a significant predictor of supratherapeutic VPC.

Optimal teicoplanin loading regimen to rapidly achieve target trough plasma concentration in critically ill patients.

Teicoplanin is used for the treatment of Methicillin-resistant Staphylococcus aureus infection. It has been demonstrated that conventional loading regimen was insufficient for teicoplanin to achieve target trough plasma concentration (Cmin  > 10 mg/L). Therefore, a Chinese expert group recommended an optimal loading dose regimen of teicoplanin to treat severe Gram-positive infection. However, there was no report about the teicoplanin concentration, and the safety and efficacy of teicoplanin therapy in Chinese patients since the consensus was published. The objective of this study was to compare the teicoplanin Cmin and clinical response in critically ill Chinese patients after the administration of conventional or optimal loading regimen, and to reveal the potential factors that may affect teicoplanin Cmin in addition to loading regimen. Fifty-five patients were retrospectively divided into two groups based on teicoplanin loading regimen: (a) CD group (conventional loading dose group, n = 18, loading dose was 400 mg); (b) OD group (optimal loading dose group, n = 37, loading dose was 800 mg). Initially, three loading doses were administered every 12 hours, while the fourth loading dose was injected 24 hours after the third dose. The maintenance dose was 400 mg (CD group) or 800 mg (OD group), respectively. The mean teicoplanin Cmin on day 2 and day 4 in the OD group was significantly higher than those in the CD group, which were 14.75 ± 5.93 mg/L vs 8.26 ± 4.87 mg/L (P < .001) and 14.90 ± 5.20 mg/L vs 9.13 ± 4.75 mg/L (P = .019), respectively. The percentages of patients in the OD group achieving the target teicoplanin Cmin on day 2 and day 4 were also significantly higher than those in the CD group, which were 83.7% vs 33.3% (P < .001) and 82.4% vs 28.6% (P = .0013), respectively. Furthermore, multivariate linear regression analysis showed that body-weight exerted significant effect on teicoplanin Cmin in the OD group. The percentage of favourable clinical response in the OD group was significantly higher than that in the CD group (83.8% vs 55.6%, P = .025). There was no difference between teicoplanin adverse effects in the two groups. The study demonstrated that the optimal loading dose regimen of teicoplanin can rapidly reach target Cmin , and result in a good clinical efficacy and low adverse effect in critically ill Chinese patients.

MicroRNA-770 affects proliferation and cell cycle transition by directly targeting CDK8 in glioma.

BACKGROUND: MicroRNAs play crucial roles in tumorigenesis and tumor progression. miR-770 has been reported to be downregulated in several cancers and affects cancer cell proliferation, apoptosis, metastasis and drug resistance. However, the role and underlying molecular mechanism of miR-770 in human glioma remain unknown and need to be further elucidated. METHODS: The expression of miR-770 in glioma tissues and cell lines was measured by quantitative real-time PCR (qRT-PCR) to explore the association of miR-770 expression with clinicopathological characteristics. The expression of CDK8 was detected by qRT-PCR and Western blotting in glioma tissues. A target prediction program and a dual-luciferase reporter assay were used to confirm that CDK8 is a target gene of miR-770. MTT and cell counting assays were used to assess the effect of miR-770 on glioma cell proliferation. The cell cycle distribution and apoptosis were examined by flow cytometry. CDK8 siRNA and overexpression were used to further confirm the function of the target gene. RESULTS: We demonstrated that miR-770 expression was downregulated in human glioma tissues and cell lines. The overexpression of miR-770 inhibited glioma cell proliferation and cell cycle G1-S transition and induced apoptosis. The inhibition of miR-770 facilitated cell proliferation and G1-S transition and suppressed apoptosis. miR-770 expression was inversely correlated with CDK8 expression in glioma tissues. CDK8 was confirmed to be a direct target of miR-770 by using a luciferase reporter assay. The overexpression of miR-770 decreased CDK8 expression at both the mRNA and protein levels, and the suppression of miR-770 increased CDK8 expression. Importantly, CDK8 silencing recapitulated the cellular and molecular effects observed upon miR-770 overexpression, and CDK8 overexpression eliminated the effects of miR-770 overexpression on glioma cells. Moreover, both exogenous expression of miR-770 and silencing of CDK8 resulted in suppression of the Wnt/ß-catenin signaling pathway. CONCLUSIONS: Our study demonstrates that miR-770 inhibits glioma cell proliferation and G1-S transition and induces apoptosis through suppression of the Wnt/ß-catenin signaling pathway by targeting CDK8. These findings suggest that miR-770 plays a significant role in glioma progression and serves as a potential therapeutic target for glioma.

Hepatic infarction induced by HELLP syndrome: a case report and review of the literature.

BACKGROUND: HELLP syndrome is a rare disease in China, and 20% of patients with severe preeclampsia have been accompanied with HELLP syndrome, which is characterized by the presence of hemolysis, elevated liver enzymes and low platelet count. CASE PRESENTATION: In this case, we reported that a patient with preeclampsia was diagnosed with HELLP syndrome. Furthermore, hepatic infarction also was found via the computed tomographic (CT) images, which showed peripheral wedge-shaped inhomogeneous low attenuation in the right hepatic lobes via plain CT scan, and the low-density shadow and mottled appearance in the same areas where vessels were seen coursing through them via contrast-enhanced CT scan. CONCLUSIONS: Besides typical clinical manifestations of the pregnant patient with preeclampsia, the typical laboratory evidences were elevated liver enzymes and thrombocytopenia. The abdominal CT scan showed imaging features of hepatic infarction, which was helpful to identify the rare complication of HELLP syndrome. Thus, we diagnosed a patient with HELLP syndrome with hepatic infarction, though the patient had no chance to do the liver biopsy.