Inhibition of visfatin alleviates sepsis-induced intestinal damage by inhibiting Hippo signaling pathway.

BACKGROUND: The aim of this study is to investigate role of Visfatin, one of the pro-inflammatory adipokines, in sepsis-induced intestinal injury and to clarify the potential mechanism. METHODS: C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to establish sepsis model in vivo. Intestinal epithelial cells were stimulated with LPS to mimic sepsis-induced intestinal injury in vitro. FK866 (the inhibitor of Visfatin) with or without XMU-MP-1 (the inhibitor of Hippo signaling) was applied for treatment. The expression levels of Visfatin, NF-κB and Hippo signaling pathways-related proteins were detected by western blot or immunohistochemistry. The intestinal cell apoptosis and intestinal injury were investigated by TUNEL staining and H&E staining, respectively. ELISA was used to determine the production of inflammatory cytokines. RESULTS: The expression of Visfatin increased in CLP mice. FK866 reduced intestinal pathological injury, inflammatory cytokines production, and intestinal cell apoptosis in sepsis mice. Meanwhile, FK866 affected NF-κB and Hippo signaling pathways. Additionally, the effects of FK866 on inflammatory response, apoptosis, Hippo signaling and NF-κB signaling were partly abolished by XMU-MP-1, the inhibitor of Hippo signaling. In vitro experiments also revealed that FK866 exhibited a protective role against LPS-induced inflammatory response and apoptosis in intestinal cells, as well as regulating NF-κB and Hippo signaling, whereas addition of XMU-MP-1 weakened the protective effects of FK866. CONCLUSION: In short, this study demonstrated that inhibition of Visfatin might alleviate sepsis-induced intestinal injury through Hippo signaling pathway, supporting a further research on Visfatin as a therapeutic target.

Ulinastatin for acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis.

AIM: To investigate the efficacy and safety of ulinastatin for patients with acute lung injury (ALI) and those with acute respiratory distress syndrome (ARDS). METHODS: A systematic review of randomized controlled trials (RCTs) of ulinastatin for ALI/ARDS was conducted. Oxygenation index, mortality rate [intensive care unit (ICU) mortality rate, 28-d mortality rate] and length of ICU stay were compared between ulinastatin group and conventional therapy group. Meta-analysis was performed by using Rev Man 5.1. RESULTS: Twenty-nine RCTs with 1726 participants were totally included, the basic conditions of which were similar. No studies discussed adverse effect. Oxygenation index was reported in twenty-six studies (1552 patients). Ulinastatin had a significant effect in improving oxygenation [standard mean difference (SMD) = 1.85, 95%CI: 1.42-2.29, P < 0.00001, I(2) = 92%]. ICU mortality and 28-d mortality were respectively reported in eighteen studies (987 patients) and three studies (196 patients). We found that ulinastatin significantly decreased the ICU mortality [I(2) = 0%, RR = 0.48, 95%CI: 0.38-0.59, number needed to treat (NNT) = 5.06, P < 0.00001], while the 28-d mortality was not significantly affected (I(2) = 0%, RR = 0.78, 95%CI: 0.51-1.19, NNT = 12.66, P = 0.24). The length of ICU stay (six studies, 364 patients) in the ulinastatin group was significantly lower than that in the control group (SMD = -0.97, 95%CI: -1.20--0.75, P < 0.00001, I(2) = 86%). CONCLUSION: Ulinastatin seems to be effective for ALI and ARDS though most trials included were of poor quality and no information on safety was provided.

[Analysis of the risk factors for early death in acute severe traumatic cervical spinal cord injury].

OBJECTIVE: To survey the risk factors for early death of patients with acute severe traumatic cervical spinal cord injury. METHODS: A retrospective analysis of data of consecutive patients with acute severe traumatic cervical spinal cord injury admitted from January 1st 1994 to October 1st 2012 were made. The patients died within 30 days or not were allocated for death group or survival group. The risk factors for early death were analyzed through univariate analysis and logistic analysis. RESULTS: Among 1093 patients with acute traumatic cervical spinal cord injury, 352 patients with severe injury were included, and the early death rate was 14.49% (51/352). The leading causes of spinal cord injury were vehicle accidents (153 cases) and falls (117 cases). The main causes of early death were respiratory failure (16 cases), multiple organ failure (MOF, 14 cases) and gastrointestinal bleeding (11 cases). Combining the results of univariate and logistic analysis, it was found that high acute physiology and chronic health evaluation II(APACHEII) score [>15, odds ratio (OR)=11.595, P=0.000], high damage level (OR=3.519, P=0.032), hyponatremia (OR=6.316, P=0.000), neurogenic shock (OR=6.209, P=0.000), pulmonary infection (OR=14.627, P=0.000) and tracheostomy (OR=8.983, P=0.000) were risk factors for early death of patients with acute severe traumatic cervical spinal cord injury, however, the impact of gender, age, surgery, fracture and dislocation, high central fever, and administration of steroids on early death of patients with acute severe traumatic cervical spinal cord injury were uncertain. CONCLUSION: The factors reflecting disease severity and occurrence of related complications were more important in predicting the early death among patients with acute severe traumatic cervical spinal cord injury, while the influence of age, surgical manipulation etc. were minor factors.

[The effect of neuromuscular blocking agents on prognosis of patients with acute respiratory distress syndrome: a meta analysis].

OBJECTIVE: To determine the effects of neuromuscular blocking agent (NMBA) on prognosis of patients with acute respiratory distress syndrome (ARDS). METHODS: PubMed database, the Cochrane Library, EMBASE, Excepta Media, CBM, CNKI and other sources were used for retrieving the pertinent literature. All randomized controlled trials (RCTs) on NMBA treating ARDS patients were enrolled. The Cochrance Collaboration's software RevMan 5.0 was used for data analysis. Two authors independently extracted data and assessed study quality using standardized instruments. RESULTS: Three studies were included in the final analysis, providing a sample of 431 patients. The combined results demonstrated a decrease in 28 days mortality [Peto odds ratio (OR) =0.57, 95% confidence interval (95%CI) 0.37-0.88, P=0.01] and lower incidence of barotrauma (OR=0.42, 95%CI 0.20-0.91,P=0.003) after NMBA treatment for patients with ARDS as compared with control group. The incidence of acquired neuromyopathy was similar between NMBA group and control group (OR=1.20, 95%CI 0.67-2.14, P=0.54). As compared with the control group at 48 hours, there was no statistical difference in ventilator parameters including total positive end expiratory pressure (PEEP, OR=0.09, 95%CI -0.50-0.68, P=0.77) and plateau pressure (Pplat, OR=0.62, 95%CI -0.32-1.57, P=0.20). There was no heterogeneity (P>0.1, I (2)<50%). At 120 hours after NMBA treatment, the total PEEP was significantly lower than that of control group (OR=-1.22, 95%CI -2.39 to -0.04, P=0.04), and the difference in Pplat showed statistical difference compared with the control group (OR=-2.61, 95%CI -4.50 to -0.73, P=0.007). CONCLUSION: Early administration of NMBA for ARDS patients results in a significant reduction in 28 days mortality, and it improves outcome.

[Effect of 45 degree angle semirecumbent position on ventilator-associated pneumonia in mechanical ventilated patients: a meta-analysis].

OBJECTIVE: To systemically analyze the effect of 45 degree angle semirecumbent position on the incidence of ventilator-associated pneumonia (VAP) and other outcomes in mechanical ventilated patients, and to evaluate whether 45 degree angle semirecumbent position is superior to 25 degree angle-30 degree angle head of bed (HOB). METHODS: The randomized controlled trials (RCTs) comparing the effect of different HOB on the outcomes of mechanical ventilated patients were searched (from 1st January 1990 to 20th July 2012) from five databases including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, China Knowledge Resource Integrated Database (CNKI), and Wanfang Database. Meta analysis was conducted using RevMan 5.0 software. RESULTS: Data extracted from five RCTs with a total of 427 patients were analyzed. The risks of developing clinically diagnosed VAP were significantly lower among the patients in semirecumbent 45 degree angle position compared to the patients in lower position [15.96% (34/213) vs. 26.64% (57/214), relative risk (RR)=0.57, 95% confidence interval (95%CI) 0.39 to 0.83, P=0.003], while no significant differences were detected between the two groups regarding the mortality rate [27.04% (53/196) vs. 28.22% (57/202), RR=0.93, 95%CI 0.68 to 1.27, P=0.66], the length of intensive care unit (ICU) stay [weighted mean difference (WMD)=-0.45, 95%CI -1.08 to 0.18, P=0.16] and the percentage of antibiotics treatment [71.11% (32/45) vs. 60.87% (28/46), RR=1.14, 95%CI 0.85 to 1.53, P=0.37]. Two of the five trials (91 patients) were included in the sub-analysis between 45 degree angle group (45 patients) and 25 degree angle-30 degree angle group (46 patients). The results showed that comparing with 25 degree angle-30 degree angle, 45 degree angle semirecumbent position had no significance in improving patients' clinical outcomes. CONCLUSION: This study proved that the clinically preferred semirecumbent 45 degree angle position did have effect in reducing the incidence of VAP, nevertheless, whether it's superior to 25 degree angle-30 degree angle needs to be confirmed by larger-scale, higher-quality RCTs.

Vesicular glutamate transporter-3 contributes to visceral hyperalgesia induced by Trichinella spiralis infection in rats.

BACKGROUND: According to a recent study, vesicular glutamate transporter-3 (VGLUT3) contributes to injury-induced mechanical hyperalgesia in mice. AIMS: The aims of the study were to investigate whether VGLUT3 is involved in visceral pain, and whether transient intestinal infection or acute cold restraint stress (ACRS) affects VGLUT3 expression levels in rats. METHODS: Changes in VGLUT3 and c-Fos proteins were evaluated in rats which received noxious colorectal distension (CRD) stimulation. Transient intestinal infection was effected by oral administration of Trichinella spiralis (T. spiralis) larvae in Brown Norway rats. On the 100th day post-infection (PI), half of the PI-rats and non infected controls were subjected to an ACRS procedure. The visceromotor response to CRD was measured using the abdominal withdrawal reflex (AWR) score. Immunofluorescence and western blot analysis were used to estimate the expression of VGLUT3 in both peripheral and central neurons. RESULTS: Noxious stimulation induced a significant increase in the expression of VGLUT3 in the L6S1 spinal dorsal horn. Compared with the control group, the pain threshold was significantly decreased in the ACRS, PI, and PI + ACRS groups. VGLUT3 expression in the L6S1 dorsal root ganglion (DRG) and spinal neurons were significantly increased in PI and PI + ACRS groups as compared with the control group. CONCLUSIONS: VGLUT3 is involved in conduction of visceral pain sensation and in visceral hyperalgesia induced by Trichinella spiralis infection in rats.

[Effects of infection and stress on transient receptor potential vanilloid receptor 1 and extracellular-regulated kinase in spinal cord of mast cell deficient rats].

OBJECTIVE: To investigate the effects of mast cells (MCs) and the relationship between the signal pathway including transient receptor potential vanilloid receptor 1 (TRPV1) and extracellular-regulated kinase (ERK) and MCs in rat models of visceral hyperalgesia triggered by infection and stress. METHODS: MCs deficient rats (WsRC Ws/Ws, Ws/Ws) and control (WsRC+/+, +/+) rats were exposed to Trichinella spiralis (T.spiralis) post-infection (PI) or submitted to acute cold restraint stress (ACRS). Visceral sensitivity was measured using the abdominal withdrawal reflex (AWR) score. Levels of TRPV1 and phosphorylated ERK1/2 (pERK1/2) proteins in L6S1 spinal cord segments were determined by Western blotting. RESULTS: Compared with control group (3.7±0.09), visceral hyperalgesia was enhanced in PI (2.52±0.13), ACRS (2.28±0.17) and PI+ACRS (2.25±0.12) groups of +/+ rats, P< 0.05. In Ws/Ws rats, compared with control group (3.25±0.20), visceral hyperalgesia was enhanced in PI (2.87± 0.14) and PI+ACRS (2.50±0.27) groups, P< 0.05, but not in ACRS group (2.97±0.22). Compared with control group (0.090±0.009), a significant increase of TRPV1 was observed in PI (0.121±0.012), ACRS (0.122±0.008) and PI+ACRS (0.129±0.008) in spinal cord of +/+ rats, P< 0.05. However, compared with control group (0.106±0.012), a significant increase of TRPV1 was observed in PI (0.140±0.008, P< 0.05) and PI+ACRS (0.156±0.010, P< 0.01) groups but not in ACRS group(0.132±0.014)in spinal cord of Ws/Ws rats. Compared with control group (0.58± 0.03), a significant increase of pERK1/2 was observed in PI (0.72±0.04), ACRS (0.75±0.04) and PI+ACRS (0.78± 0.01) in spinal cord of +/+ rats, P< 0.01. However, compared with control group (0.59±0.04), a significant increase of pERK1/2 was observed in PI (0.72±0.04, P< 0.05) and PI+ACRS (0.74±0.04, P< 0.05) groups but not in ACRS group(0.132±0.014)in spinal cord of Ws/Ws rats. CONCLUSION: The visceral hyperalgesia was enhanced in rats induced by T.spiralis infection and ACRS, however, the increased visceral hyperalgesia in rats induced by ACRS was dependent on MCs. The signal pathway proteins including TRPV1 and pERK1/2 were increased in rats induced by T.spiralis infection and ACRS, but the sensitizing TRPV1 or mobilizing ERK1/2 phosphorylation via a MCs-dependent mechanism plays an important role in ACRS-induced visceral hyperalgesia rats.

[Combined effects of elevated body position on gastroesophageal reflux and intra-abdominal pressure in mechanical ventilated patients].

OBJECTIVE: To investigate the combined effects of elevated body position on gastroesophageal reflux and intra-abdominal pressure (IAP) in patients undergoing mechanical ventilation (MV) who were receiving enteral nutrition, and to find out their proper height of head of bed. METHODS: The continuous pH-impedance and bladder pressure (reflecting IAP) at different body positions (0 degree angle, 20 degree angle, 30 degree angle, 45 degree angle) in 6 hours were monitored in 41 MV and enteral nutrition supported patients. The patients who did not have previous gastroesophageal reflux disease (GERD) were admitted to intensive care unit (ICU) of Peking University Third Hospital from March 2010 to December 2010 were included in the study. RESULTS: (1)The most common fluid reflux were weak acid and non-acid reflux. Acid reflux was rare. When elevating the body position from 0 degree to 30 degree angle, the accumulated numbers of these 3 kinds of reflux were declined significantly, and the percentage of high esophageal reflux decreased significantly (numbers of reflux: 0 degree angle: 20 degree angle: 30 degree angle: acid 3.0: 2.0: 1.0, weak acid 13.0: 9.0: 6.0, non-acid 4.0: 3.0: 2.0; percentage of high esophageal reflux: 0 degree angle: 20 degree angle: 30 degree angle: acid 16.00%: 9.00%: 7.84%; weak acid 68.40%: 47.40%: 46.69%; non-acid 15.61%: 9.82%: 8.89%, P<0.05 or P<0.01). But when elevating the body position from 30 degree angle to 45 degree angle, no more significant changes in the numbers of reflux were found, instead, the percentage of high esophageal reflux increased (numbers of reflux 30 degree angle: 45 degree angle: acid 1.0: 1.0, weak acid 6.0: 5.0, non-acid 2.0: 2.0, all P>0.05; percentage of high esophageal reflux 30 degree angle: 45 degree angle: acid 7.84%: 12.00%, weak acid 46.69%: 52.29%, non-acid 8.89%: 17.58%, all P<0.05).(2) Four of the 41 patients (9.76%, 4/41) were found to have intra-abdominal hypertension (IAH) at 0 degree angle body position, with one patient at IV degree (IAH>25 mm Hg, 1 mm Hg= 0.133 kPa). With the patients' body position elevated, the IAP appeared to be further increased [the IAP (mm Hg) at 0 degree angle, 20 degree angle, 30 degree angle, 45 degree position were 10.32±3.48, 11.33±3.71, 13.55±3.58 and 18.25±3.82, respectively P<0.01]; With each level of elevation of the body position, the increasing rate was enhanced markedly [the increasing rate of IAP from 0 degree angle to 20 degree angle, 20 degree angle to 30 degree angle and 30 degree to 45 degree were (9.74±3.05)%, ( 19.60±5.67 )% and (34.73±7.67)%, respectively, the difference between any two groups was significant, all P<0.01]. When elevating the body position from 30 degree to 45 degree angle, the numbers of patients with different levels of IAH were increased significantly too (30 degree angle: 45 degree angle: leveI: 5: 8; leveII: 2: 5; level III: 3: 5; level IV: 2: 3, P<0.05 or P<0.01). CONCLUSION: Although elevation of the body position of MV patients can reduce gastroesophageal reflux, it also increase the IAP. When the body position is elevated to 45 degree angle, the number of reflux is not reduced effectively, while the rate of high esophageal reflux and the patients' IAP are increased significantly, indicating that 30 degree might be the proper body position for the MV patients receiving enteral nutrition.

Alteration of cholinergic and peptidergic neurotransmitters in rat ileum induced by acute stress following transient intestinal infection is mast cell dependent.

BACKGROUND: Mast cells are implicated in the development of irritable bowel syndrome (IBS), which is associated with the activation of the "neural-immune" system. The aim of this study was to investigate the role of mast cells in the remodeling of cholinergic and peptidergic neurotransmitters induced by acute cold restriction stress (ACRS) post infection (PI) using mast cell deficient rats (Ws/Ws) and their wild-type controls (+/+). METHODS: Transient intestinal infection was initiated by giving 1500 Trichinella spiralis (T.S.) larvae by gavage. ACRS was induced for 2 hours at day 100 PI. Samples of terminal ilea were prepared for H&E staining, mast cell counting and activation and assessment of IL-1beta and IL-10. RESULTS: When infected, both strains of rats experienced an acute infectious stage followed by a recovery. Histological scores were significantly higher in infected rats compared with those of the non-infected controls at day 10 PI (10 day-PI vs. control: +/+: 2.75+/-0.17 vs. 0.42+/-0.09; Ws/Ws: 2.67+/-0.67 vs. 0.50+/-0.34; P<0.01). In +/+ rats, post-infection ACRS induced the formation of low-grade inflammation, represented by the imbalance of IL-1beta and IL-10 (IL-1beta: PI+ACRS vs. control: (1812.24+/-561.61) vs. (1275.97+/-410.21) pg/g, P<0.05; IL-10: PI+ACRS vs. control: (251.9+/-39.8) vs. (255.3+/-24.7) pg/g, P>0.05), accompanied by hyperplasia and activation of mast cells (PI+ACRS vs. control: 58.8+/-19.2 vs. 28.0+/-7.6; P<0.01). The balance between acetylcholine (ACh) and substance P (SP) was also disturbed (ACh: PI+ACRS vs. control: (743.94+/-238.72) vs. (1065.68+/-256.46) pg/g, P<0.05; SP: PI+ACRS vs. control: (892.60+/-231.12) vs. (696.61+/-148.61) pg/g, P<0.05). Nevertheless, similar changes of IL-1beta/IL-10 and ACh/SP were not detected in Ws/Ws rats. CONCLUSION: The imbalance of ACh/SP, together with the activation of mucosal immunity induced by post-infection ACRS were lacking in mast cell deficient rats, which supports the premise that mast cells play an important role in cholinergic and peptidergic remodeling in the ileum of rats.

[Establishment of irritable bowel syndrome rat model by combination of intestinal infection with Trichinella spiralis and acute stress].

OBJECTIVE: To establish the irritable bowel syndrome (IBS) rat model by the combination of acute stress and transient intestinal infection with Trichinella spiralis (T.S.). METHODS: The rat model of acute cold restraint stress post-infection (PI + ACRS) was established as following: the intestinal infection with 1500 T.S. in 1 ml saline to adult male BN rats was performed at Day 0 by gastric lavage. Then a 2-hour stimulus of ACRS was administered at Day 100. Age matched transiently infected without stress rats (PI) and normal rats served as controls (CON) (n = 6, for each). After anesthesia, all the rats underwent colonic manometry in vivo at Day 100. The colonic pressures at 3 different states (baseline for 20 min; 1 ml balloon distension stimulation for 5 min and 2 ml balloon distension stimulation for 20 min) were traced with a 5-minute interval between each two. The following parameters were recorded: (1) Duration (Dur.): total time of contractions during each state. (2) Maximum (Max.): highest amplitude of constructional waves (mm Hg). (3) Area: area under contraction waves. (4) Number (Num.): frequencies of contraction wave during each state. The visceromoter response to colorectal distension (CRD) was analyzed at Day 100 post-infection. And the distension volume of AWR 3 was detected for 5 times with a 20-min interval in each rat. RESULTS: The histological damage of intestine induced by T.S. infection is transient. Although such acute infectious features as epithelial edema, hyperemia and marked eosinophil infiltration appeared at Day 10 PI, the histological changes almost recovered at Day 100 PI in both the PI group and the PI + ACRS group. Both the stimuli of transient infection and the ACRS post-infection induced intestinal dysmotility and visceral hypersensitivity. The ACRS post infection further worsened the transiently induced infection. The parameters of Num, Max and Area in the PI + ACRS group were all significantly higher than those of the PI group [Max: (41 +/- 17) mm Hg vs (22 +/- 6) mm Hg, P = 0.000; Area: (7693 +/- 2822) mm Hg.s vs (5092 +/- 1687) mm Hgxs, P = 0.000; Num: 9.5 +/- 2.6 vs 6.6 +/- 3.1, P = 0.000]; so was the distension volume of AWR3 [(2.25 +/- 0.29) ml vs (2.52 +/- 0.32) ml, P = 0.004]. As compared with the range of normal values from controls, the abnormality rates of motility parameters and visceral threshold in PI + ACRS group also had an larger increment than those of the PI group (PI + ACRS: 50.0% - 87.5% and 100% respectively, PI: 25.0% - 37.5% and 90.0% respectively). CONCLUSION: The pathophysiological changes in the PI + ACRS rats are consistent with those of IBS. Aggravated by psychological factors, these rats reproduce the symptoms of intestinal dysmotility and visceral hypersensitivity. A proper animal model has been established for the investigation of IBS.

Multiterawatt laser system based on optical parametric chirped pulse amplification.

A compact multiterawatt laser system based on optical parametric chirped pulse amplification is demonstrated. Chirped pulses are amplified from 20 pJ to 900 mJ by two lithium triborate optical parametric preamplifiers and a final KDP optical parametric power amplifier with a pump energy of 5 J at 532 nm from Nd:YAG-Nd:glass hybrid amplifiers. After compression, we obtained a final output of 570-mJ-155-fs pulses with a peak power of 3.67 TW, which is the highest output power from an optical parametric chirped pulse amplification laser, to the best of our knowledge.