The Current Situation of Anaesthesia for Hysteroscopy in Mainland China: A National Survey.

Purpose: The need for anaesthesia or analgesia for performing hysteroscopy remains debatable. This study aimed to conduct an overview of the situation of anaesthesia for hysteroscopy in mainland China. Methods: Two questionnaires were separately designed for anaesthesiologists and gynaecologists and distributed to every medical institution that performed hysteroscopic procedures on patients with infertility in mainland China. Electronic questionnaires were distributed via WeChat, and data on anaesthesia regimen, monitoring parameters, procedure number, and other information were collected. Results: Reproductive technology is conducted by 536 institutions in mainland China. The survey received 491 responses from anaesthetists (91.6%) and 436 from gynaecologists (81.3%). In 2021, 552,225 hysteroscopies were conducted in 268 medical centres. The average percentage of hysteroscopy under anaesthesia is 63.8% in 2021, wherein 47.3% of institutions have an anaesthesia percentage of >75%. Propofol and opioid analgesics, such as fentanyl and sufentanil, were the most commonly used intravenous anaesthetics. All sedations were performed by anaesthesiologists. Monitoring parameters included pulse oxygen saturation (98.9%), electrocardiogram (91.6%) and noninvasive blood pressure (91.3%). An anaesthesiologist-to-operating room ratio of <1 was observed in 31.3% of medical institutions. Surprisingly, 52.4% of medical institutions performing hysteroscopy had no postanaesthesia care unit (PACU). Most institutions with PACU were equipped with independent oxygen sources, suction and monitors. Both rigid and flexible hysteroscopes (rigid hysteroscope, 45.1%; flexible hysteroscope, 4.5%; both types, 50.4%) were used, and the hysteroscopic diameter was ≤5 mm in 60.3% of medical centres. Conclusions: China performs a large number of hysteroscopies, and sedation is the most frequently used anesthesia regimen. However, issues such as inadequate emergency support devices, insufficient personnel and weak resuscitation management after anaesthesia, have been observed.

Mechanical Ventilation Exacerbates Poly (I:C) Induced Acute Lung Injury: Central Role for Caspase-11 and Gut-Lung Axis.

Background: The mechanisms by which moderate tidal volume ventilation (MTV) exacerbates preexisting lung injury are unclear. We hypothesized that systemic endotoxemia via the gut-lung axis would lead to non-canonical and canonical inflammasome activation and pyroptosis in a two-hit model involving polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of dsRNA and MTV and that this would associate with acute lung injury (ALI). Methods: Anesthetized mice were administered Poly(I:C) intratracheally and then 6 h later, they were mechanically ventilated for 4 h with otherwise non-injurious MTV (10ml/kg). Changes in intestinal and alveolar capillary permeability were measured. Further documentation of ALI was assessed by evans blue albumin permeability, protein and IL-1 family concentration in bronchoalveolar lavage fluid (BALF) or plasma, and histopathology in cohorts of wildtype (WT), whole body genetically ablated caspase-11 (caspase-11-/-), caspase-1/caspase-11 double knockout (caspase-1/11-/-), gasdermin D (GSDMD)-/-, nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3)-/- and advanced glycosylation end product-specific receptor (RAGE) -/- mice. Results: Non-injurious MTV exacerbated the mild lung injury associated with Poly(I:C) administration. This included the disruption of alveolar-capillary barrier and increased levels of interleukin (IL)-6, high mobility group proteins 1 (HMGB-1), IL-1ß in BALF and IL-18 in plasma. Combined (Poly(I:C)-MTV) injury was associated with increase in gastrointestinal permeability and endotoxin in plasma and BALF. Poly(I:C)-MTV injury was sensitive to caspase-11 deletion with no further contribution of caspase-1 except for maturation and release of IL-18 (that itself was sensitive to deletion of NLRP3). Combined injury led to large increases in caspase-1 and caspase-11. Genetic ablation of GSDMD attenuated alveolar-capillary disruption and release of cytokines in combined injury model. Conclusions: The previously noted exacerbation of mild Poly(I:C)-induced ALI by otherwise non-injurious MTV is associated with an increase in gut permeability resulting in systemic endotoxemia. The gut-lung axis resulted in activation of pulmonary non-canonical (cytosolic mediated caspase-11 activation) and canonical (caspase-1) inflammasome (NLRP3) mediated ALI in this two-hit model resulting in GSDMD sensitive alveolar capillary barrier disruption, pyroptosis (alveolar macrophages) and cytokine maturation and release (IL-1ß; IL-18). Pharmacologic strategies aimed at disrupting communication between gut and lung, inhibition of inflammasomes or GSDMD in pyroptosis may be useful in ALI.

The HIV protease inhibitor Saquinavir attenuates sepsis-induced acute lung injury and promotes M2 macrophage polarization via targeting matrix metalloproteinase-9.

Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.

WISP1 and TLR4 on Macrophages Contribute to Ventilator-Induced Lung Injury.

Injurious mechanical ventilation has been shown to directly affect pulmonary and systemic immune responses. How these responses propagate or attenuate remains unknown. The goal of this study was to further determine whether toll-like receptor (TLR) 4 and WNT1-inducible signaling pathway protein 1 (WISP1) could contribute to injurious mechanical ventilation, especially focusing on the role of macrophages during experimental ventilator-induced lung injury. A prospective, randomized, and controlled animal study was designed, and male, wild-type (WT) C57BL/6 mice, TLR4 knockout (TLR4-/-), and lyzTLR4 knockout (lyzTLR4-/-) mice aging 8~12 weeks were used. Animals were anesthetized and randomized to spontaneous breathing (SB) group or to high tidal volume (VT, 20 ml/kg) mechanical ventilation (HTV) group. Histological evaluation, alveolar-capillary permeability of Evan's blue albumin (EBA), WISP1 protein levels, macrophage inflammatory protein-2 (MIP-2), and interleukin-6 (IL-6) in plasma and bronchoalveolar lavage fluid (BALF) concentrations were analyzed. HTV group was associated with a significant increase of WISP1 and EBA ratio in C57BL/6 mice, a significant decrease of WISP1 protein levels, and a significant decrease of IL-6, MIP-2 in plasma, and BALF concentrations of pro-inflammatory cytokines in TLR4-/- and lyzTLR4-/- knockout mice. In TLR4-/- mice and lyzTLR4-/- mice, there were also significant differences between SB group and HTV group in terms of H&E score and EBA ratio and level of pro-inflammation cytokines. The entire TLR4-targeted mice could further improve various inflammatory changes and damages when compared with lyzTLR4-targeted mice. What is more, TLR4-/- mice and lyzTLR4-/- mice reacted differently to rWISP1 and/or BMMC treated. TLR4-/- mice had no response to rWISP1, while lyzTLR4-/- mice still showed drastic response to both treatments. TLR4 and WISP1, especially the former one, on macrophages could contribute to releasing of pro-inflammatory cytokines during ventilator-induced lung injury. Injurious mechanical ventilation may result in an immune response which is similar to that of infection.

The IL-33-ST2 Pathway Contributes to Ventilator-Induced Lung Injury in Septic Mice in a Tidal Volume-Dependent Manner.

Mechanical ventilation (MV) is frequently employed to manage respiratory failure in sepsis patients and is required for the surgical management of intra-abdominal sepsis. The impact of MV varies dramatically depending on tidal volume, with even moderate tidal volume (MTV) ventilation leading to ventilator-induced lung injury, whereas low tidal volume (LTV) ventilation protects against sepsis-induced acute respiratory distress syndrome. Interleukin (IL)-33 is known to contribute to lung injury in sepsis and its release can be induced by mechanical stress. To determine the relationship between the IL-33-suppression of tumorigenicity 2 (ST2) pathway and patterns of lung injury associated with MV in sepsis, mice were subjected to cecal ligation and puncture (CLP) followed 6 h later by either MTV (10 mL/kg) or LTV (6 mL/kg) ventilation for 4 h. MTV and LTV ventilation alone for 4 h had no impact on lung injury. MTV markedly exacerbated lung injury and inflammation, while LTV significantly suppressed these parameters in septic mice. Lung and plasma levels of IL-33 ST2 were significantly elevated by CLP alone at 10 h. MTV caused further and significant increases in IL-33 and sST2 levels, while LTV significantly suppressed levels induced by CLP. Deletion of IL-33 or ST2 prevented the increase in lung injury and inflammation induced by MTV in septic mice, while administration of recombinant IL-33 in the airway reversed the protection seen with LTV. Taken together, these findings implicate the IL-33-ST2 pathway in the pro-inflammatory changes induced by the mechanical ventilation that leads to lung injury in the setting of intra-abdominal sepsis in a tidal volume-dependent manner.

WISP1 mediates lung injury following hepatic ischemia reperfusion dependent on TLR4 in mice.

BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is a common pathological phenomenon, which causes hepatic injury as well as remote organ injuries such as the lung. Several mediators, such as oxidative stress, Ca2+ overload and neutrophil infiltration, have been implied in the pathogenesis of liver and remote organ injuries following reperfusion. WNT1 inducible signaling pathway protein 1 (WISP1) is an extracellular matrix protein that has been associated with the onset of several malignant diseases. Previous work in our group has demonstrated WISP1 is upregulated and contributes to proinflammatory cascades in hepatic IRI. However, the role of WISP1 in the pathogenesis of lung injury after hepatic IRI still remains unknown. METHODS: Male C57BL/6 mice were used to examine the expression and role of WISP1 in the pathogenesis of lung injuries after hepatic IRI and explore its potential mechanisms in mediating lung injuries. RESULTS: We found WISP1 was upregulated in lung tissues following hepatic IRI. Treatment with anti-WISP1 antibody ameliorated lung injuries with alteration of cytokine profiles. Administration with rWISP1 aggravated lung injuries following hepatic IRI through excessive production of proinflammatory cytokines and inhibition of anti-inflammatory cytokines. CONCLUSIONS: In this study, we concluded that WISP1 contributed to lung injuries following hepatic IRI through TLR4 pathway.

Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1-αvß5 integrin pathway in TLR4-mediated inflammation and injury.

BACKGROUND: High tidal volume ventilation of healthy lungs or exacerbation of existing acute lung injury (ALI) by more moderate mechanical ventilation (MTV) produces ventilator-induced lung injury. It is less clear whether extrapulmonary sepsis sensitizes the lung to MTV. METHODS: We used a two-hit model of cecal ligation and puncture (CLP) followed 12 h later by MTV (10 ml/kg; 6 h) to determine whether otherwise noninjurious MTV enhances CLP-induced ALI by contrasting wildtype and TLR4-/- mice with respect to: alveolar-capillary permeability, histopathology and intrapulmonary levels of WNT-inducible secreted protein 1 (WISP1) and integrin ß5; plasma levels of cytokines and chemokines (TNF-α, IL-6, MIP-2, MCP-1) and intrapulmonary neutrophil infiltration; and other inflammatory signaling via intrapulmonary activation of JNK, p38 and ERK. A separate cohort of mice was pretreated with intratracheal neutralizing antibodies to WISP1, integrin ß5 or IgG as control and the presented phenotyping repeated in a two-hit model; there were 10 mice per group in these first three experiments. Also, isolated peritoneal macrophages (PM) from wildtype and TLR4-/-, MyD88-/- and TRIF-/- mice were used to identify a WISP1-TLR4-integrin ß5 pathway; and the requisite role of integrin ß5 in WISP1-induced cytokine and chemokine production in LPS-primed PM was examined by siRNA treatment. RESULTS: MTV, that in itself did not cause ALI, exacerbated increases in alveolar-capillary permeability, histopathologic scoring and indices of pulmonary inflammation in mice that previously underwent CLP; the effects of this two-hit model were abrogated in TLR4-/- mice. Attendant with these findings was a significant increase in intrapulmonary WISP1 and integrin ß5 in the two-hit model. Anti-WISP1 or anti-integrin ß5 antibodies partially inhibited the two-hit phenotype. In PM, activation of TLR4 led to an increase in integrin ß5 expression that was MyD88 and NF-κB dependent. Recombinant WISP1 increased LPS-induced cytokine release in PM that was inhibited by silencing either TLR4 or integrin ß5. CONCLUSIONS: These data show for the first time that otherwise noninjurious mechanical ventilation can exacerbate ALI due to extrapulmonary sepsis underscoring a potential interactive contribution of common events (sepsis and mechanical ventilation) in critical care, and that a WISP1-TLR4-integrin ß5 pathway contributes to this phenomenon.

Sepsis Upregulates CD14 Expression in a MyD88-Dependent and Trif-Independent Pathway.

An overwhelming immune response, particularly from macrophages, plays a critical role in survival and organ damage in sepsis patients. Toll-like receptors (TLRs) are important receptors to recognize the conserved motifs expressed by invading bacteria. The TLRs except TLR3 signal via a MyD88-dependent pathway. TLR3 uses a TRIF-dependent pathway, while TLR4 uses both MyD88 and TRIF-dependent pathways. Previous studies indicated that CD14 was necessary for TLRs-dependent production of pro-inflammatory cytokines. Blocking CD14 protected against the deleterious systemic inflammatory response associated with sepsis. The aim of this study was to determine the signaling pathway of TLR activation-induced CD14 expression in models of polymicrobial sepsis and in peritoneal macrophages. We found that CD14 expression was upregulated in the lung, liver, and kidney of septic mice induced by cecal ligation puncture. In cultured peritoneal macrophages, specific agonists for all TLRs, except for TLR3, increased CD14 expression. Lipopolysaccharide-induced upregulation of CD14 was abolished in peritoneal macrophages from MyD88 KO mice but increased in TRIF inhibitor, resveratrol pretreated wild-type macrophages. Moreover, MyD88 KO, but not TRIF KO mice, showed a decreased CD14 expression in the tissue of septic mice, which was associated with a strongly attenuated inflammatory response and increased survival rate. These data suggest that a MyD88-dependent and TRIF-independent pathway of TLR is activated in upregulating CD14 expression under septic conditions. This study deciphers a critical cross-talk between TLRs and CD14.

High-mobility group box 1 protein is involved in the protective effect of Saquinavir on ventilation-induced lung injury in mice.

Saquinavir (SQV) is the first FDA approved HIV protease inhibitor. Previous studies showed that SQV can limit Toll-like receptor-4 (TLR4)-mediated inflammatory pathway and nuclear factor-κB (NF-κB) activation, thereby playing a protective role in many kinds of diseases. High-mobility group box 1 (HMGB1) has been identified as an inflammatory mediator and it might express its toxicity in a short period of time in ventilator-induced lung injury (VILI). In this study, C57BL/6 mice were randomly divided into four groups (n = 10): control group and control with SQV group (Con + SQV) were spontaneous breath. HTV group (HTV) received high tidal volume ventilation (HTV) for 4 h. HTV with SQV group (HTV + SQV) were pretreated with 5 mg/kg of SQV for 7 days before HTV. Mice were sacrificed after 4 h of HTV. Lung wet/dry weight (W/D) ratio, alveolar-capillary permeability to Evans blue albumin (EBA), cell counts, total proteins in bronchoalveolar lavage fluid (BALF), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) level in BALF and lung tissue, and lung histopathology were examined. Our results showed that HTV caused significant lung injury and NF-κB activation, which was correlated with the increase of TNF-α and IL-6 levels in BALF and plasma. SQV pretreatment significantly attenuated pulmonary inflammatory injury, as well as NF-κB activation. These findings indicate that the protective effect of SQV may be associated with the inhibition of NF-κB activation and HMGB1 expression in mice.

TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury.

Acute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AMΦ) recognize the molecular constituents of pathogens and activate the host's innate immune responses. Numerous studies have documented the importance of TLR-TLR cross talk, but few studies have specifically addressed the relationship between TLR4 and TLR3. We explored a novel mechanism of TLR3 up-regulation that is induced by LPS-TLR4 signaling in a dose- and time-dependent manner in AMΦ from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4-/- and Myd88-/- mice and following pretreatment with a NF-κB inhibitor. The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. Our study demonstrates that the synergistic effect between TLR4 and TLR3 in macrophages is an important determinant in acute lung injury and, more importantly, that TLR3 up-regulation is dependent on TLR4-MyD88-NF-κB signaling. These results raise the possibility that bacterial infections can induce sensitivity to viral infections, which may have important implications for the therapeutic manipulation of the innate immune system.

Saquinavir Ameliorates Liver Warm Ischemia-Reperfusion-Induced Lung Injury via HMGB-1- and P38/JNK-Mediated TLR-4-Dependent Signaling Pathways.

Liver ischemia and reperfusion (I/R) induce local and distant tissue injuries, contributing to morbidity and mortality in a wider range of pathologies. This is especially seen under uncontrolled aseptic inflammatory conditions, leading to injury of remote organs, such as lung injury, and even failure. Saquinavir (SQV) is a kind of HIV protease inhibitor that possesses an anti-inflammatory property. In this study, we investigated whether SQV suppresses Toll-like receptor 4- (TLR4-) dependent signaling pathways of high-mobility group box 1 (HMGB1) and P38/JNK, conferring protection against murine liver I/R-induced lung injury. To investigate our hypothesis, C57BL/6 mice and TLR4 knockout mice (TLR4-/-) were used to perform the study. SQV administration markedly attenuated remote lung tissue injury after 1-hour ischemia and 6-hour reperfusion of the liver. To our expectation, SQV attenuated I/R-induced lung edema, hyperpermeability, and pathological injury. The beneficial effects of SQV were associated with decreased levels of circulating and lung tissue inflammatory cytokines, such as IL-6, IL-1ß, TNF-α, and iNOS. The protective effect of SQV was also associated with decreased lung tissue expression of HMGB1, TLR-4, and p-P38/JNK, but not p-ERK in wild-type liver I/R mice. Overall, this study demonstrated a new role of SQV, facilitating negative regulation of HMGB1- and P38/JNK-mediated TLR-4-dependent signaling pathways, conferring protection against liver I/R-induced lung injury.

WISP1-αvß3 integrin signaling positively regulates TLR-triggered inflammation response in sepsis induced lung injury.

We recently noted that the matricellular protein WISP1 contributes to sepsis induced acute lung injury (ALI) via integrin ß6. In the current study, we pursued further aspects of WISP1 modulation of TLR signaling in lungs of mice after sepsis and TLR4 mediated release of TNF-α in macrophages. After confirming that TLR4 and CD14 are critical in transducing sepsis mediated ALI, we now demonstrate that intrapulmonary αvß3 is increased by polymicrobrial sepsis in a TLR4, CD14 dependent fashion. Comparison of cultured macrophages revealed that WISP1 increased release of TNF-α from RAW264.7 cells with baseline expression of αvß3, but primary cultures of peritoneal macrophages (PMø) required activation of TLR4 to induce de novo synthesis of αvß3 enabling WISP1 to stimulate release of TNF-α. The specific requirement for ß3 integrin was apparent when the effect of WISP1 was lost in PMø isolated from ß3(-/-) mice. WISP1 enhanced TLR4 mediated ERK signaling and U0126 (an ERK inhibitor) blocked LPS induced ß3 integrin expression and WISP1 enhanced TNF-α release. Collectively these data suggest that WISP1-αvß3 integrin signaling is involved in TLR4 pathways in macrophages and may be an important contributor to TLR4/CD14 mediated inflammation in sepsis induced lung injury.

MECHANICAL VENTILATION AUGMENTS POLY(I:C)INDUCED LUNG INJURY VIA A WISP1-INTEGRIN ß3 DEPENDENT PATHWAY IN MICE.

Mechanical ventilation can improve hypoxemia, but can also cause the so-called ventilator-induced lung injury (VILI). Polyinosinic-polycytidylic acid (poly(I:C)), an analogue of natural double strand RNA virus, can induce lung inflammation. The purpose of this study was to determine whether moderate tidal volume mechanical ventilation (MTV) augments Poly(I:C)-induced lung injury, and if so, the mechanism responsible for it. Poly(I:C) (2µg/g) were instilled intratracheally in C57BL/6J wide type (WT) mice. They were then randomized to MTV (10ml/kg tidal volume) or spontaneous breath. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected 4h later for various measurements. Our results showed that MTV did not cause significant injury in normal lungs, but augmented Poly(I:C)-induced lung injury. The expression level of WNT-induced secreted protein 1 (WISP1) was consistent with lung injury, and the amplification of lung injury by MTV can be alleviated by anti-WISP1 antibody treatment. MTV further increased Poly(I:C)-induced integrin ß3 expression in the lung. And co-immunoprecipitation (Co-IP) results suggested there was an interaction between WISP1 and ß3. WISP1 significantly increased Poly(I:C)-induced TNF-α production in macrophages isolated from WT mice but not in macrophages isolated from ß3 knock-out mice. Co-treatment with WISP1 and Poly(I:C) markedly increased the phosphorylation of extracellular signal-related kinase (ERK) in macrophages. Pretreating macrophages with an ERK inhibitor, U0126, dose-dependently antagonized WISP's synergistic effect on Poly(I:C)-induced TNF-α release. In conclusion, MTV exaggerates Poly(I:C)-induced lung injury in a WISP1 and integrin ß3 dependent manner, involving, at least part, the activation of the ERK pathway. The WISP1-integrin ß3 pathway could be an important target for novel therapy.

WISP1 mediates hepatic warm ischemia reperfusion injury via TLR4 signaling in mice.

Wnt-induced secreted protein-1 (WISP1) is an extracellular matrix protein that has been reported in cancer researches. Our previous studies on WISP1 implied it could be a harmful mediator in septic mice. However, its role in liver ischemia reperfusion (I/R) injury is unknown. This study investigated the effects of WISP1 on liver I/R damage. Male C57BL/6 wild-type mice were used to undergo 60 min segmental (70%) ischemia. WISP1 expression was measured after indicated time points of reperfusion. Anti-WISP1 antibody was injected intraperitoneally to mice. Toll-like receptor 4 (TLR4) knockout mice and TIR-domain-containing adaptor inducing interferon-ß (TRIF) knockout mice were adopted in this study. WISP1 was significantly enhanced after 6 h of reperfusion when compared with sham treated mice and significantly decreased either by TLR4 knockout mice or TRIF knockout mice. Anti-WISP1 antibody significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), pathological changes and pro-inflammatory cytokine levels in the mice following I/R. Furthermore, significantly increased serum transaminase levels were found in C57 wild-type mice treated with recombinant WISP1 protein, but not found in TLR4 knockout or TRIF knockout mice subjected to liver I/R. Taken together, WISP1 might contribute to hepatic ischemia reperfusion injury in mice and possibly depends on TLR4/TRIF signaling.

Analgesia for total knee arthroplasty: a meta-analysis comparing local infiltration and femoral nerve block.

Patients frequently experience postoperative pain after a total knee arthroplasty; such pain is always challenging to treat and may delay the patient's recovery. It is unclear whether local infiltration or a femoral nerve block offers a better analgesic effect after total knee arthroplasty.We performed a systematic review and meta-analysis of randomized controlled trials to compare local infiltration with a femoral nerve block in patients who underwent a primary unilateral total knee arthroplasty. We searched Pubmed, EMBASE, and the Cochrane Library through December 2014. Two reviewers scanned abstracts and extracted data. The data collected included numeric rating scale values for pain at rest and pain upon movement and opioid consumption in the first 24 hours. Mean differences with 95% confidence intervals were calculated for each end point. A sensitivity analysis was conducted to evaluate potential sources of heterogeneity.While the numeric rating scale values for pain upon movement (MD-0.62; 95%CI: -1.13 to -0.12; p=0.02) in the first 24 hours differed significantly between the patients who received local infiltration and those who received a femoral nerve block, there were no differences in the numeric rating scale results for pain at rest (MD-0.42; 95%CI:-1.32 to 0.47; p=0.35) or opioid consumption (MD 2.92; 95%CI:-1.32 to 7.16; p=0.18) in the first 24 hours.Local infiltration and femoral nerve block showed no significant differences in pain intensity at rest or opioid consumption after total knee arthroplasty, but the femoral nerve block was associated with reduced pain upon movement.

Analgesia for total knee arthroplasty: a meta-analysis comparing local infiltration and femoral nerve block

Patients frequently experience postoperative pain after a total knee arthroplasty; such pain is always challenging to treat and may delay the patient’s recovery. It is unclear whether local infiltration or a femoral nerve block offers a better analgesic effect after total knee arthroplasty.We performed a systematic review and meta-analysis of randomized controlled trials to compare local infiltration with a femoral nerve block in patients who underwent a primary unilateral total knee arthroplasty. We searched Pubmed, EMBASE, and the Cochrane Library through December 2014. Two reviewers scanned abstracts and extracted data. The data collected included numeric rating scale values for pain at rest and pain upon movement and opioid consumption in the first 24 hours. Mean differences with 95% confidence intervals were calculated for each end point. A sensitivity analysis was conducted to evaluate potential sources of heterogeneity.While the numeric rating scale values for pain upon movement (MD-0.62; 95%CI: -1.13 to -0.12; p=0.02) in the first 24 hours differed significantly between the patients who received local infiltration and those who received a femoral nerve block, there were no differences in the numeric rating scale results for pain at rest (MD-0.42; 95%CI:-1.32 to 0.47; p=0.35) or opioid consumption (MD 2.92; 95%CI:-1.32 to 7.16; p=0.18) in the first 24 hours.Local infiltration and femoral nerve block showed no significant differences in pain intensity at rest or opioid consumption after total knee arthroplasty, but the femoral nerve block was associated with reduced pain upon movement.

Effect of saphenous nerve block for postoperative pain on knee surgery: a meta-analysis.

Early post-operative mobilization is important both to reduce immobility-related complications and to get the best functional result following surgery on knee. We hypothesized that saphenous nerve block would reduce pain in this patient category compared with placebo injection. In this study, two reviewers independently searched the databases of PubMed, EMBASE, and Cochrane Library (last performed on 12 October, 2014) to retrieve eligible randomized controlled clinical trials. The primary outcomes were visual analog scale (VAS) pain scores within 24 hours after operation when at rest and at an active flexion of knee. Mean difference (MD) or odds ratio (OR) with 95% confidence intervals (CIs) was calculated for each end point. Subgroup analysis was calculated to evaluate potential sources of heterogeneity. Nine randomized controlled trials were retrieved and analyzed. We found that VAS pain scores at rest within postoperative 24 hours were significantly decreased in saphenous nerve block group than that in placebo group (MD = -0.79; 95% CI -1.35 to -0.22; P = 0.007), as well as VAS pain scores at an active flexion of knee within postoperative 24 hours (MD = -0.92; 95% CI -1.61 to -0.22; P = 0.010). In addition, compared to placebo injection group, saphenous nerve block resulted in significantly less morphine consumption during the first postoperative 24 hours (MD = -6.56; 95% CI -11.26 to -1.86; P = 0.006). To conclude, this meta-analysis suggests that saphenous nerve block has an advantage in pain relief both at an active flexion of knee and at rest after knee surgery. Further studies are still wanted to validate these conclusions.

RGD peptides protects against acute lung injury in septic mice through Wisp1-integrin ß6 pathway inhibition.

Acute lung injury is a common consequence of sepsis, a life-threatening inflammatory response caused by severe infection. In this study, we elucidate the attenuating effects of synthetic Arg-Gly-Asp-Ser peptides (RGDs) on acute lung injury in a sepsis mouse model. We further reveal that the beneficial effects of RGDs stem from their negative regulation of the Wisp1 (WNT1-inducible signaling pathway)-integrin ß6 pathway. After inducing sepsis using cecal ligation and puncture (CLP), mice were randomized into experimental and control groups, and survival rates were recorded over 7 days, whereas only 20% of mice subjected to CLP survived when compared with untreated controls; the addition of RGDs to this treatment regimen dramatically increased the survival rate to 80%. Histological analysis revealed acute lung injury in CLP-treated mice, whereas those subjected to the combined treatment of CLP and RGDs showed a considerable decrease in lung injury severity. The addition of RGDs also dramatically attenuated other common sepsis-associated effects, such as increased white blood cell number in bronchoalveolar lavage fluid and decreased pulmonary capillary barrier function. Furthermore, treatment with RGDs decreased the serum and bronchoalveolar lavage fluid levels of inflammatory cytokines such as tumor necrosis factor α and interleukin 6, contrary to the CLP treatment alone that increased the levels of these proteins. Interestingly, however, RGDs had no detectable effect on bacterial invasion following sepsis induction. In addition, mice treated with RGDs showed decreased levels of wisp1 and integrin ß6 when compared with CLP-treated mice. In the present study, a linkage between Wisp1 and integrin ß6 was evaluated in vivo. Most strikingly, RGDs resulted in a decreased association of Wisp1 with integrin ß6 based on coimmunoprecipitation analyses. These data suggest that RGDs ameliorate acute lung injury in a sepsis mouse model by inhibiting the Wisp1-integrin ß6 pathway.

Morphine with adjuvant ketamine versus higher dose of morphine alone for acute pain: a meta-analysis.

PURPOSE: Ketamine is currently the N-methyl-D-aspartate receptor channel blocker in clinical use. Morphine in pain management is usually limited by adverse effect such as nausea and vomiting. Adjuvant treatment with ketamine may be value in giving better analgesia with fewer adverse effects. The purpose of this meta-analysis was to evaluate the differences when patients received morphine with adjuvant ketamine (MK) compared with higher dose of morphine (MO) for acute pain. METHODS: The PubMed, EMBASE and the Cochrane Library databases were searched (Last search performed on July 1, 2014) by two reviewers independently. Data were extracted independently by the same two individuals who searched the studies. RESULTS: A total of 7 trials involving 492 patients were included in the current analysis. We found pain scores were lower in the MK group compared to the MO group [MD 2.19, 95% CI (1.24, 3.13) P<0.00001]. And more patients in the MO required diclofenac [OR 1.97, 95% CI (1.06, 3.67) P=0.03]. Furthermore, morphine plus ketamine can reduced post-operative nausea and vomiting (PONV) [OR 3.71, 95% CI (2.37, 5.80) P<0.00001]. Importantly, the wakefulness scores for the MK group were consistently and significantly better than those for the MO group [MD -1.53, 95% CI (-2.67, -0.40) P=0.008]. CONCLUSION: The use of ketamine plus 1/4~2/3 the dose of morphine is better than higher dose of morphine alone in reducing pain scores, and rescuing analgesic requirement. It also improved PONV and wakefulness.