Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 µM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

Reliability Evaluation Method for Array Antenna Considering Performance Changes.

The existing array antenna reliability evaluation method based on the n/k system is analyzed. As the failed T/R module's influence on the array antenna's performance is not considered, the reliability of the array antenna is overestimated. To improve the accuracy of the array antenna reliability evaluation, the performance changes caused by T/R failures in different locations are considered. The reliability evaluation method considering the performance changes is established. The performance and probability of the array antenna's state are calculated, and accurate reliability is obtained by calculating all the available state's probabilities. The complexity of the reliability evaluation method is analyzed, and the reliability evaluation method for large-scale array antennae is established. The large-scale array antenna is divided into several subarrays. The performance and reliability of each subarray are analyzed, and the array antenna's reliability is calculated through subarrays. The array antenna's performance changes are considered with the proposed method, the overestimation problem of the existing reliability evaluation method is solved, and the accuracy of the array antenna reliability evaluation is improved.

[Research progress on mitochondrial copper homeostasis imbalance and fibrosis diseases].

Copper ions serve as co-factors for various enzymes and participate in multiple cellular processes. Mitochondria are essential copper reservoirs within the cell. Previous reviews have extensively summarized the association between mitochondrial copper homeostasis imbalance and hematologic disorders, cardiomyopathies, and skeletal myopathies. However, there is limited information regarding its association with organ fibrosis. This article outlines the role and mechanism of disrupted mitochondrial copper homeostasis in fibrotic diseases, and systematically elaborates copper absorption and transport, as well as the regulation of copper homeostasis within mitochondria. It focuses on the impacts of mitochondrial copper overload and deficiency on fibrotic diseases, and the application of copper chelators as potential anti-fibrotic therapeutic approaches.

COX17 restricts renal fibrosis development by maintaining mitochondrial copper homeostasis and restoring complex IV activity.

Renal fibrosis relies on multiple proteins and cofactors in its gradual development. Copper is a cofactor of many enzymes involved in renal microenvironment homeostasis. We previously reported that intracellular copper imbalance occurred during renal fibrosis development and was correlated with fibrosis intensity. In this study, we investigated the molecular mechanisms of how copper affected renal fibrosis development. Unilateral ureteral obstruction (UUO) mice were used for in vivo study; rat renal tubular epithelial cells (NRK-52E) treated with TGF-ß1 were adapted as an in vitro fibrotic model. We revealed that the accumulation of copper in mitochondria, rather than cytosol, was responsible for mitochondrial dysfunction, cell apoptosis and renal fibrosis in both in vivo and in vitro fibrotic models. Furthermore, we showed that mitochondrial copper overload directly disrupted the activity of respiratory chain complex IV (cytochrome c oxidase), but not complex I, II and III, which hampered respiratory chain and disrupted mitochondrial functions, eventually leading to fibrosis development. Meanwhile, we showed that COX17, the copper chaperone protein, was significantly upregulated in the mitochondria of fibrotic kidneys and NRK-52E cells. Knockdown of COX17 aggravated mitochondrial copper accumulation, inhibited complex IV activity, augmented mitochondrial dysfunction and led to cell apoptosis and renal fibrosis, whereas overexpression of COX17 could discharge copper from mitochondria and protect mitochondrial function, alleviating renal fibrosis. In conclusion, copper accumulation in mitochondria blocks complex IV activity and induces mitochondrial dysfunction. COX17 plays a pivotal role in maintaining mitochondrial copper homeostasis, restoring complex IV activity, and ameliorating renal fibrosis.

[Comparison of coagulation function between adrenocorticotropic hormone independent Cushing syndrome and nonfunctional adrenal adenoma and its influence factors].

OBJECTIVE: To investigate the coagulation function indicators and identify influence factors of hypercoagulability in patients with adrenocorticotropic hormone (ACTH) independent Cushing syndrome (CS). METHODS: In our retrospective study, the electronic medical records system of Peking University First Hospital was searched for the patients diagnosed with ACTH independent CS on discharge from January 2014 to June 2019. Nonfunctional adrenal adenoma patients were chosen as control group and matched 1 ∶1 by body mass index (BMI), gender, and discharge date. Clinical features and coagulation function indicators were compared between the two groups. RESULTS: In the study, 171 patients were included in each group. Compared with control group, activated partial thromboplastin time (APTT), and prothrombin time (PT) in ACTH independent CS group were significantly lower [(29.22±3.39) s vs. (31.86±3.63) s, P < 0.001; (29.22±3.39) s vs. (31.86±3.63) s, P < 0.001], and both D-dimer and fibrin degradation products (FDP) levels were significantly higher (P < 0.05). Percentage of APTT levels under the lower limit of reference range in the CS patients was significantly higher than that in nonfunctional group (21.6% vs. 3.5%, P < 0.001). Percentage of D-dimer levels over the upper limit of reference range in the CS patients was significantly higher than that in nonfunctional group (13.5% vs. 6.6%, P=0.041). There were three patients with deep venous thrombosis and one patient with pulmonary embolism in CS group, however none was in control group. The area under curve (AUC) of serum cortisol rhythm (8:00, 16:00 and 24:00) levels was negatively associated with the levels of PT (r=-0.315, P < 0.001) and APTT (r=-0.410, P < 0.001), and positively associated with FDP (r=0.303, P < 0.001) and D-dimer levels (r=0.258, P < 0.001). There were no differences in coagulation function indicators among different histopathologic subgroups (adrenocortical adenoma, adrenocortical hyperplasia, oncocytic adenoma, adrenocortical carcinoma). With Logistic regression analysis, the AUC of cortisol and glycosylated hemoglobin A1c (HbA1c) levels were independent risk factors for hypercoagulability in the ACTH independent CS patients (P < 0.05). CONCLUSION: ACTH independent CS patients were more likely in hypercoagulable state compared with nonfunctional adrenal adenoma, especially in ACTH independent CS patients with higher levels of cortisol AUC and HbA1c. These patients should be paid attention to for the hypercoagulability and thrombosis risk.

Circular RNA circUbe2k promotes hepatic fibrosis via sponging miR-149-5p/TGF-ß2 axis.

Abundant regulatory genes and complex circuits involving non-coding RNAs (ncRNAs) monitor the formation and development of hepatic fibrosis (HF). Circular RNAs (circRNAs) are a class of RNAs generated from protein coding genes by back-splicing, playing crucial roles in various pathological processes, including HF. However, little is known about mechanisms of action of circRNAs, let alone in HF. In this study, we found circUbe2k enhanced in CCl4 -induced HF mice and LX-2 cells stimulated with TGF-ß1, regulating the development of HF. Restraining the expression of circUbe2k inhibited α-SMA and Col1α1 expression in CCl4 -induced HF mice and in LX-2 cells stimulated with TGF-ß1. Furthermore, inhibiting circUbe2k expression reduced hepatic stellate cells (HSCs) activation and proliferation in vivo and in vitro. Mechanistically, we demonstrated a direct interaction between circUbe2k and miR-149-5p, which results in the modulation of TGF-ß2 expressions. Together, circUbe2k may act as a "catalyst" of HSCs activation and HF through the circUbe2k/miR-149-5p/TGF-ß2 axis. Our results provide unprecedented evidence for a significant role for circUbe2k to serve as a potential biomarker for HF therapy.

Prophylactic Penehyclidine Inhalation for Prevention of Postoperative Pulmonary Complications in High-risk Patients: A Double-blind Randomized Trial.

BACKGROUND: Postoperative pulmonary complications are common. Aging and respiratory disease provoke airway hyperresponsiveness, high-risk surgery induces diaphragmatic dysfunction, and general anesthesia contributes to atelectasis and peripheral airway injury. This study therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces the incidence of pulmonary complications in high-risk patients over the initial 30 postoperative days. METHODS: This single-center double-blind trial enrolled 864 patients age over 50 yr who were scheduled for major upper-abdominal or noncardiac thoracic surgery lasting 2 h or more and who had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher. The patients were randomly assigned to placebo or prophylactic penehyclidine inhalation from the night before surgery through postoperative day 2 at 12-h intervals. The primary outcome was the incidence of a composite of pulmonary complications within 30 postoperative days, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis. RESULTS: A total of 826 patients (mean age, 64 yr; 63% male) were included in the intention-to-treat analysis. A composite of pulmonary complications was less common in patients assigned to penehyclidine (18.9% [79 of 417]) than those receiving the placebo (26.4% [108 of 409]; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). Bronchospasm was less common in penehyclidine than placebo patients: 1.4% (6 of 417) versus 4.4% (18 of 409; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011). None of the other individual pulmonary complications differed significantly. Peak airway pressures greater than 40 cm H2O were also less common in patients given penehyclidine: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). The incidence of other adverse events, including dry mouth and delirium, that were potentially related to penehyclidine inhalation did not differ between the groups. CONCLUSIONS: In high-risk patients having major upper-abdominal or noncardiac thoracic surgery, prophylactic penehyclidine inhalation reduced the incidence of pulmonary complications without provoking complications.

Hesperetin derivative decreases CCl4 -induced hepatic fibrosis by Ptch1-dependent mechanisms.

Hepatic fibrosis (HF), a continuous wound-healing response of the liver to repeated injuries, is characterized by abnormal extracellular matrix (ECM) accumulation. Hepatic stellate cells (HSCs) are considered a major cell type for ECM production. However, recent evidence indicates the lack of effective treatments for HF. Hesperetin, a Traditional Chinese Medicine monomer, has been isolated from the fruit peel of Citrusaurantium L. (Rutaceae). Growing evidence suggests the partial function of hesperetin in HF treatment. A hesperetin derivative (HD) was synthesized in our laboratory to increase the bioavailability and the water solubility of hesperetin. In this study, we detected the functions of HD in a mouse model of CCl4 -induced HF and transforming growth factor-ß1-stimulated HSC-T6 cells, in vivo and in vitro. HD reduced histological damage and CCl4 -induced HF. Moreover, HD interference was associated with the activation of indicators in HSC-T6 cells, showing that HD is involved in HSCs activation in HF. Mechanistically, the Hedgehog pathway is involved in the HD treatment of HF, and HD may attenuate the aberrant expression of patched1. In conclusion, the studies indicate that HD may function as a potential antifibrotic Traditional Chinese Medicine monomer in HF therapy.

Effect of a carbohydrate-rich beverage on rate of cesarean delivery in primigravidae with epidural labor analgesia: a multicenter randomized trial.

BACKGROUND: Labor represents a period of significant physical activity. Inefficient energy supply may delay labor process and even lead to cesarean delivery. Herein we investigated whether ingestion of a carbohydrate-rich beverage could reduce cesarean delivery in laboring women with epidural analgesia. METHODS: This multicenter randomized trial was conducted in obstetrician-led maternity units of nine tertiary hospitals in China. Primigravidae with single term cephalic pregnancy who were preparing for vaginal birth under epidural analgesia were randomized to intake a carbohydrate-rich beverage or commercially available low-carbohydrate beverages during labor. The primary outcome was the rate of cesarean delivery. Secondary outcomes included maternal feeling of hunger, assessed with an 11-point scale where 0 indicated no hunger and 10 the most severe hunger, and maternal and neonatal blood glucose after childbirth. RESULTS: Between 17 January 2018 and 20 July 2018, 2008 women were enrolled and randomized, 1953 were included in the intention-to-treat analysis. The rate of cesarean delivery did not differ between the two groups (11.3% [111/982] with carbohydrate-rich beverage vs. 10.9% [106/971] with low-carbohydrate beverages; relative risk 1.04, 95% CI 0.81 to 1.33; p = 0.79). Women in the carbohydrate-rich beverage group had lower subjective hunger score (median 3 [interquartile range 2 to 5] vs. 4 [2 to 6]; median difference - 1; 95% CI - 1 to 0; p < 0.01); their neonates had less hypoglycemia (1.0% [10/968] vs. 2.3% [22/956]; relative risk 0.45; 95% CI 0.21 to 0.94; p = 0.03) when compared with those in the low-carbohydrate beverage group. They also had higher rates of maternal hyperglycemia (6.9% [67/965] vs. 1.9% [18/953]; p < 0.01) and neonatal hyperglycemia (9.2% [89/968] vs. 5.8% [55/956]; p < 0.01), but none required special treatment. CONCLUSIONS: For laboring primigravidae with epidural analgesia, ingestion of a carbohydrate-rich beverage compared with low-carbohydrate beverages did not reduce cesarean delivery, but relieved maternal hunger and reduced neonatal hypoglycemia at the expense of increased hyperglycemia of both mothers and neonates. Optimal rate of carbohydrate supplementation remains to be determined. TRIAL REGISTRATION: www.chictr.org.cn ; identifier: ChiCTR-IOR-17011994 ; registered on 14 July 2017.

Long-term Survival after Combined Epidural-General Anesthesia or General Anesthesia Alone: Follow-up of a Randomized Trial.

BACKGROUND: Experimental and observational research suggests that combined epidural-general anesthesia may improve long-term survival after cancer surgery by reducing anesthetic and opioid consumption and by blunting surgery-related inflammation. This study therefore tested the primary hypothesis that combined epidural-general anesthesia improves long-term survival in elderly patients. METHODS: This article presents a long-term follow-up of patients enrolled in a previous trial conducted at five hospitals. Patients aged 60 to 90 yr and scheduled for major noncardiac thoracic and abdominal surgeries were randomly assigned to either combined epidural-general anesthesia with postoperative epidural analgesia or general anesthesia alone with postoperative intravenous analgesia. The primary outcome was overall postoperative survival. Secondary outcomes included cancer-specific, recurrence-free, and event-free survival. RESULTS: Among 1,802 patients who were enrolled and randomized in the underlying trial, 1,712 were included in the long-term analysis; 92% had surgery for cancer. The median follow-up duration was 66 months (interquartile range, 61 to 80). Among patients assigned to combined epidural-general anesthesia, 355 of 853 (42%) died compared with 326 of 859 (38%) deaths in patients assigned to general anesthesia alone: adjusted hazard ratio, 1.07; 95% CI, 0.92 to 1.24; P = 0.408. Cancer-specific survival was similar with combined epidural-general anesthesia (327 of 853 [38%]) and general anesthesia alone (292 of 859 [34%]): adjusted hazard ratio, 1.09; 95% CI, 0.93 to 1.28; P = 0.290. Recurrence-free survival was 401 of 853 [47%] for patients who had combined epidural-general anesthesia versus 389 of 859 [45%] with general anesthesia alone: adjusted hazard ratio, 0.97; 95% CI, 0.84 to 1.12; P = 0.692. Event-free survival was 466 of 853 [55%] in patients who had combined epidural-general anesthesia versus 450 of 859 [52%] for general anesthesia alone: adjusted hazard ratio, 0.99; 95% CI, 0.86 to 1.12; P = 0.815. CONCLUSIONS: In elderly patients having major thoracic and abdominal surgery, combined epidural-general anesthesia with epidural analgesia did not improve overall or cancer-specific long-term mortality. Nor did epidural analgesia improve recurrence-free survival. Either approach can therefore reasonably be selected based on patient and clinician preference.

Density- and moisture-dependent effects of arbuscular mycorrhizal fungus on drought acclimation in wheat.

Arbuscular mycorrhizal fungus (AMF) is widely viewed as an ecosystem engineer to help plants adapt to adverse environments. However, a majority of the previous studies regarding AMF's eco-physiological effects are mutually inconsistent. To clarify this fundamental issue, we conducted an experiment focused on wheat (Triticum aestivum L.) plants with or without AMF (Funneliformis mosseae) inoculation. Two water regimes (80% and 40% field water capacity, FWC80 (CK) and FWC40 (drought stress) and four planting densities (6 or 12 plants per pot as low densities, 24 or 48 plants per pot as high densities) were designed. AMF inoculation did not show significant effects on shoot biomass, grain yield, and water use efficiency (WUE) under the low densities, regardless of water regimes. However, under the high densities, AMF inoculation significantly decreased shoot biomass, grain yield and WUE in FWC80, while it significantly increased these parameters in FWC40, showing density and/or moisture-dependent effects of AMF on wheat performance. In FWC40, the relationships between reproductive biomass (y-axis) vs. vegetative biomass (x-axis) (R-V), and between grain biomass (y-axis, sink) vs. leaf biomass (x-axis, source) fell into a typical allometric pattern (α > 1, P < 0.001), and the AMF inoculation significantly increased the values of α. Yet in FWC80, they were in an isometric pattern (α ≈ 1, P < 0.001) and AMF addition had no significant effects on α. Similarly, AMF did not significantly change the isometric relationship between leaf biomass (i.e., metabolic rate) and shoot biomass (body size) in FWC80, while it significantly decreased the α of allometric relationship between both of them in FWC40 (α > 1, P < 0.001). We therefore, sketched a generalized model of R-V and sink-source relationships as affected by AMF, in which AMF inoculation might enhance the capabilities of sink acquisition and utilization under drought stress, while having no significant effect under the well watered conditions. Our findings demonstrate dual density- and moisture-dependent effects of AMF on plant development and provide new insights into current ecological applications of AMF as an ecosystem engineer.

Impact of dexmedetomidine supplemented analgesia on delirium in patients recovering from orthopedic surgery: A randomized controlled trial.

BACKGROUND: Dexmedetomidine promotes normal sleep architecture; the drug also improves analgesia. We therefore tested the hypothesis that supplementing intravenous analgesia with dexmedetomidine reduces delirium in older patients recovering from orthopedic surgery. METHODS: In this double-blinded randomized controlled trial, we enrolled 712 older (aged 65-90 years) patients scheduled for major orthopedic surgery. Postoperative analgesia was provided by patient-controlled intravenous sufentanil, supplemented by randomly assigned dexmedetomidine (1.25 µg/mL) or placebo, for up to three days. The primary outcome was the incidence of delirium assessed twice daily with the Confusion Assessment Method. Among secondary outcomes, pain severity was assessed twice daily and sleep quality once daily, each with an 11-point scale where 0 = no pain/the best possible sleep and 10 = the worst pain/the worst possible sleep. RESULTS: The incidence of postoperative delirium was 7.3% (26 of 354) with placebo and 4.8% (17 of 356) with dexmedetomidine; relative risk 0.65, 95% CI 0.36 to 1.18; P = 0.151. Dexmedetomidine reduced pain both at rest (median difference -1 to 0 points, P ≤ 0.001) and with movement (-1 points, P < 0.001) throughout the first 5 postoperative days; it also improved subjective sleep quality during the first 3 postoperative days: day one median difference -1 point (95% CI -1 to 0), P = 0.007; day two 0 point (-1 to 0), P = 0.010; and day three 0 point (-1 to 0), P = 0.003. The incidence of adverse events was similar in each group. CONCLUSIONS: Supplementing sufentanil intravenous analgesia with low-dose dexmedetomidine did not significantly reduce delirium, but improved analgesia and sleep quality without provoking adverse events. TRIAL REGISTRATION: www.chictr.org.cn : ChiCTR1800017182 (Date of registration: July 17, 2018); ClinicalTrials.gov: NCT03629262 (Date of registration: August 14, 2018).

PLK1 regulates hepatic stellate cell activation and liver fibrosis through Wnt/ß-catenin signalling pathway.

As an outcome of chronic liver disease, liver fibrosis involves the activation of hepatic stellate cells (HSCs) caused by a variety of chronic liver injuries. It is important to explore approaches to inhibit the activation and proliferation of HSCs for the treatment of liver fibrosis. PLK1 is overexpressed in many human tumour cells and has become a popular drug target in tumour therapy. Therefore, further study of the function of PLK1 in the cell cycle is valid. In the present study, we found that PLK1 expression was elevated in primary HSCs isolated from CCl4 -induced liver fibrosis mice and LX-2 cells stimulated with TGF-ß1. Knockdown of PLK1 inhibited α-SMA and Col1α1 expression and reduced the activation of HSCs in CCl4 -induced liver fibrosis mice and LX-2 cells stimulated with TGF-ß1. We further showed that inhibiting the expression of PLK1 reduced the proliferation of HSCs and promoted HSCs apoptosis in vivo and in vitro. Furthermore, we found that the Wnt/ß-catenin signalling pathway may be essential for PLK1-mediated HSCs activation. Together, blocking PLK1 effectively suppressed liver fibrosis by inhibiting HSC activation, which may provide a new treatment strategy for liver fibrosis.

Appropriate Source Control and Antifungal Therapy are Associated with Improved Survival in Critically Ill Surgical Patients with Intra-abdominal Candidiasis.

BACKGROUND: Intra-abdominal candidiasis (IAC) is the predominant type of invasive candidiasis with high mortality in surgical intensive care patients. The purpose of this study was to investigate the impact of appropriate source control and antifungal therapy on the outcomes of critically ill surgical patients with IAC. METHODS: This was a retrospective single-center cohort study. Adult surgical patients who were admitted to the intensive care unit and diagnosed with IAC from January 1, 2003, to December 31, 2016, were enrolled. The patients' data including risk factors of IAC, infection-related information, antifungal treatment and 30-day outcomes were collected. The primary endpoint was 30-day mortality. A COX proportional hazards model was used to analyze the association between appropriate treatment and 30-day survival. RESULTS: A total of 82 patients were included in the analysis. Of these, 45 (54.9%) were complicated with septic shock at IAC diagnosis. Types of IAC included peritonitis (61.0%), intra-abdominal abscesses (23.2%) and biliary tract infections (15.9%). Of the included patients, 53 (64.6%) received appropriate source control and 44 (53.7%) appropriate antifungal therapy. Compared with patients with neither of these treatments, appropriate source control (HR 0.08, 95% CI 0.02-0.30; P < 0.001), appropriate antifungal therapy (HR 0.14, 95% CI 0.04-0.55; P = 0.005), and a combination of these treatments (HR 0.02, 95% CI 0.00-0.08; P < 0.001) were associated with reduced risk of death within 30 days after IAC diagnosis. CONCLUSION: For critically ill surgical patients with IAC, both appropriate source control and appropriate antifungal therapy were associated with reduced risk of 30-day mortality, and the protective effects of the two appropriate treatments were additive.

Intraoperative hypotension is associated with increased postoperative complications in patients undergoing surgery for pheochromocytoma-paraganglioma: a retrospective cohort study.

BACKGROUND: Dramatic hemodynamic fluctuation occurs frequently during surgery for pheochromocytoma or paraganglioma. However, the criteria of intraoperative hemodynamic instability vary widely, and most of them were defined arbitrarily but not according to patients' prognosis. The objective was to analyze the relationship between different thresholds and durations of intraoperative hyper-/hypotension and the risk of postoperative complications in patients undergoing surgery for pheochromocytoma or paraganglioma. METHODS: This was a retrospective single-center cohort study performed in a tertiary care hospital from January 1, 2005 to December 31, 2017. Three hundred twenty-seven patients who underwent surgery for pheochromocytoma or paraganglioma, of which the diagnoses were confirmed by postoperative pathologic examination, were enrolled. Those who were less than 18 years, underwent surgery involving non-tumor organs, or had incomplete data were excluded. The primary endpoint was a composite of the occurrence of AKI or other complications during hospital stay after surgery. Multivariate Logistic regression models were used to analyze the association between different thresholds and durations of intraoperative hyper-/hypotension and the development of postoperative complications. RESULTS: Forty three (13.1%) patients developed complications during hospital stay after surgery. After adjusting for confounding factors, intraoperative hypotension, defined as systolic blood pressure (SBP) of ≤95 mmHg for ≥20 min (OR 3.211; 99% CI 1.081-9.536; P = 0.006), SBP of ≤90 mmHg for ≥20 min (OR 3.680; 98.8% CI 1.107-12.240; P = 0.006), SBP of ≤85 mmHg for ≥10 min (OR 3.975; 98.3% CI 1.321-11.961; P = 0.003), and SBP of ≤80 mmHg for ≥1 min (OR 3.465; 95% CI 1.484-8.093; P = 0.004), were associated with an increased risk of postoperative complications. On the other hand, intraoperative hypertension was not significantly associated with the development of postoperative complications. CONCLUSIONS: For patients undergoing surgery for pheochromocytoma or paraganglioma, intraoperative hypotension is associated with increased postoperative complications; and the harmful effects are level- and duration-dependent. The effects of intraoperative hypertension need to be studied further.

Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Despite optimization of renin-angiotensin-aldosterone system (RAAS) inhibition, patients with immunoglobulin A nephropathy (IgAN) and persistent proteinuria remain at risk for kidney failure. We evaluated the efficacy and safety of hydroxychloroquine (HCQ), an immunomodulator, when added to the treatment regimen of patients with IgAN. STUDY DESIGN: Double-blind, randomized, placebo-controlled, phase 2 clinical trial. SETTING & PARTICIPANTS: Participants had IgAN (proteinuria with protein excretion of 0.75-3.5g/d and estimated glomerular filtration rate>30mL/min/1.73m2) and were receiving optimized RAAS inhibitor therapy. INTERVENTIONS: Patients were randomly assigned 1:1 to receive daily oral HCQ or a placebo for 6 months. OUTCOMES: The primary outcome was percentage change in proteinuria between baseline and 6 months. RESULTS: 60 participants (mean estimated glomerular filtration rate, 53.8mL/min/1.73m2; median urine protein excretion, 1.7g/d) were recruited and randomly assigned to receive HCQ (n=30) or placebo (n=30). Percentage change in proteinuria at 6 months was significantly different between the HCQ group and the placebo group (-48.4% [IQR, -64.2%, -30.5%] vs 10.0% [IQR, -38.7%, 30.6%]; P<0.001, respectively). At 6 months, median proteinuria level was significantly lower in the HCQ group than in the placebo group (0.9 [IQR, 0.6, 1.0] g/d vs 1.9 [IQR, 0.9, 2.6] g/d; P=0.002, respectively). No serious adverse events were recorded during the study in either study group. LIMITATIONS: The short treatment period and lack of postwithdrawal observations limit conclusions about long-term renoprotective efficacy and safety. CONCLUSIONS: HCQ in addition to optimized RAAS inhibition significantly reduced proteinuria in patients with IgAN over 6 months without evidence of adverse events. These findings require confirmation in larger treatment trials. FUNDING: This study was supported by grants from a government entity, the Capital of Clinical Characteristics, and the Applied Research Fund. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02942381.

Handover of anesthesia care is associated with an increased risk of delirium in elderly after major noncardiac surgery: results of a secondary analysis.

In patients undergoing major surgery, complete handover of intraoperative anesthesia care is associated with adverse postoperative outcomes including high mortality and more major complications. The purpose of this study was to explore the association between the intraoperative complete handover between anesthesiologists and the occurrence of postoperative delirium. This was a secondary analysis of the database of a previously published clinical trial. Seven hundred patients aged 65 years or older, who were admitted to the intensive care unit after noncardiac surgery, were included. Delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit twice daily during the first 7 postoperative days. Other postoperative outcomes were also monitored. The association between the intraoperative complete handover of anesthesia care and the development of postoperative delirium was analyzed with a logistic regression model. Of the 700 enrolled patients, 111 (15.9%) developed postoperative delirium within 7 days. After correction for confounding factors, intraoperative complete handover between anesthesiologists was associated with an increased risk of postoperative delirium (OR 1.787, 95% CI 1.012-3.155, P = 0.046). Patients with intraoperative complete handover also had higher incidence of non-delirium complications (P = 0.003) and stayed longer in hospital after surgery (P = 0.002). For elderly patients admitted to the intensive care unit after noncardiac surgery, intraoperative complete handover of anesthesia care was associated with an increased risk of postoperative delirium. Chinese Clinical Trial Registry ( http://www.chictr.org.cn ): ChiCTR-TRC-10000802.

Alterations of CCR5 and CCR7 expression on donor peripheral blood T cell subsets after mobilization with rhG-CSF correlate with acute graft-versus-host disease.

To investigate the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on chemokine receptors and explore the potential mechanism of rhG-CSF inducing immune tolerance, ninety-seven donor and recipient pairs undergoing family-donor allogeneic hematopoietic stem cell transplantation were studied. The results indicated that different donors showed great disparities in expression changes after mobilization. Multivariate analysis revealed that both HLA mismatching and CCR7 downregulation on donors' CD4+ T cells after mobilization were independent risk factors for acute graft-versus-host disease (GVHD). In contrast, CCR5 downregulation on CD4+ T cells was associated with reduced incidence of acute GVHD. In conclusion, rhG-CSF mobilization could lead to differential regulation of chemokine receptors expression on T cell subsets in different donors. Downregulation of CCR5 and upregulation of CCR7 expression on donor CD4+ T cells might protect recipients from acute GVHD. This finding may provide a promising new strategy for the prevention and treatment of acute GVHD.

Overproduction of Mitochondrial Fission Proteins in Membranous Nephropathy in Children.

BACKGROUND/AIMS: The molecules involved in nephrotic syndrome (NS) have not been fully clarified. Mitochondrial fission proteins are found to be involved in podocyte injury in vitro. Increased glomerular expression of mitochondrial fission proteins was found in adriamycin nephropathy in our previous study. Whether or not mitochondrial fission proteins are involved in podocyte injury in NS is not clear. This study explored the glomerular expression and possible pathological significance of mitochondrial fission-associated proteins, including dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1), in children with NS. METHODS: Eighteen children with primary NS, including 6 with minimal change disease, 6 with focal segmental glomerulosclerosis, 6 with membranous nephropathy, 6 children with isolated haematuria and 3 normal controls were included. The glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1, urinary protein measurements, and podocyte mitochondrial density under electron microscopy were investigated and compared. RESULTS: Glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1 was mainly increased in children with NS with membranous nephropathy. No relationship was found between glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1 and podocyte mitochondrial density or urinary protein measurements. CONCLUSION: Glomerular overproduction of Drp1, phospho-Drp1 (Ser 616) and Fis1 occurred mainly in children with membranous nephropathy. The pathological significance deserves further investigation.

IP3R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model.

BACKGROUND: The mechanism of podocyte apoptosis is not fully understood. In addition, the role of the inositol 1,4,5-triphosphate receptor (IP3R)/glucose-regulated protein 75 (Grp75)/voltage-dependent anion channel 1 (VDAC1)/mitochondrial calcium uniporter (MCU) calcium regulation axis, which is located at sites of endoplasmic reticulum (ER) mitochondria coupling, in the mechanism of podocyte apoptosis is unclear. This study aimed to understand the roles of this axis in podocyte apoptosis and explore potential targets for podocyte protection. METHODS: The expression of IP3R, Grp75, VDAC1, and MCU and mitochondrial Ca2+ were analyzed during Adriamycin- or angiotensin II-induced apoptosis in cultured mouse podocytes. The interaction between IP3R, Grp75, and VDAC1 was investigated using co-immunoprecipitation experiments. The effects of IP3R, Grp75, and MCU agonists and antagonists on mitochondrial Ca2+ and apoptosis were investigated in cultured podocytes. The podocyte-protective effects of an MCU inhibitor were further investigated in rats with Adriamycin-induced nephropathy. RESULTS: Increased expression of IP3R, Grp75, VDAC1 and MCU, enhanced interaction among the IP3R-Grp75-VDAC1 complex, mitochondrial Ca2+ overload, and increased active caspase-3 levels were confirmed during Adriamycin- or angiotensin II-induced mouse podocyte apoptosis. Agonists of this axis facilitated mitochondrial Ca2+ overload and podocyte apoptosis, whereas specific antagonists against IP3R, Grp75, or MCU prevented mitochondrial Ca2+ overload and podocyte apoptosis. A specific MCU inhibitor prevented Adriamycin-induced proteinuria and podocyte foot process effacement in rats. CONCLUSIONS: This study identified a novel pathway in which the IP3R-Grp75-VDAC1-MCU calcium regulation axis mediated podocyte apoptosis by facilitating mitochondrial Ca2+ overload. Antagonists that inhibit Ca2+ transfer from ER to mitochondria protected mouse podocytes from apoptosis. An MCU inhibitor protected podocytes and decreased proteinuria in rats with Adriamycin-induced nephropathy. Therefore, antagonists to this pathway have promise as novel podocyte-protective drugs.