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Abstract Background CD24+CK19+/CD24+SOX9+ resident liver cells are activated and expanded after chronic liver injury in a ductular reaction. However, the sources and functions of these cells in liver damage remain disputed. Results The current study combined genetic lineage tracing with in vitro small-molecule-based reprogramming to define liver progenitor cells (LPCs) derived from hepatic parenchymal and non-parenchymal tissues. tdTom+ hepatocytes were isolated from ROSA26 tdTomato mice following AAV8-Tbg-Cre-mediated recombination, EpCAM+ biliary epithelial cells (BECs) from wild-type intrahepatic bile ducts and ALB/GFP−EpCAM− cells were isolated from Alb CreERT /R26 GFP mice. A cocktail of small molecules was used to convert the isolated cells into LPCs. These in vitro cultured LPCs with CD24 and SOX9 expression regained the ability to proliferate. Transcriptional profiling showed that the in-vitro cultured LPCs derived from the resident LPCs in non-parenchymal tissues expressed Lipocalin-2 (Lcn2) at high levels. Accordingly, endogenous Cd24a + Lcn2 + LPCs were identified by integration of sc-RNA-sequencing and pathological datasets of liver dysfunction which indicates that LPCs produced by ductular reactions might also originate from the resident LPCs. Transplantation of in-vitro cultured Cd24a + Lcn2 + LPCs into CCl4-induced fibrotic livers exacerbated liver damage and dysfunction, possibly due to LCN2-dependent macrophage inflammatory response. Conclusions CD24+LCN2+ LPCs constituted the expanding ductular reaction and contributed to macrophage-mediated inflammation in chronic liver damage. The current findings highlight the roles of LPCs from distinct origins and expose the possibility of targeting LPCs in the treatment of chronic hepatic diseases. Graphical Abstract

Abstract Background Whether anesthesia type is associated with the surgical outcome of Hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) remains to be determined. This study aims to investigate the impact of volatile inhalational anesthesia (INHA) versus total IV anesthesia (TIVA) on the survival outcomes in HCC patients with PVTT. Methods A cohort of in-patients whom were diagnosed of HCC with PVTT in Eastern Hepatobiliary Surgery Hospital, Shanghai, China, from January 1, 2008 to December 24, 2012 were identified. Surgical patients receiving the INHA and TIVA were screened out. The overall survival (OS), recurrence-free survival (RFS) and several postoperative adverse events were compared according to anesthesia types. Results A total of 1513 patients were included in this study. After exclusions are applied, 263 patients remain in the INHA group and 208 in the TIVA group. Patients receiving INHA have a lower 5-year overall survival rate than that of patients receiving TIVA [12.6% (95% CI, 9.0 to 17.3) vs. 17.7% (95% CI, 11.3 to 20.8), P = 0.024]. Results of multivariable Cox-regression analysis also identify that INHA anesthesia is significantly associated with mortality and cancer recurrence after surgery compare to TIVA, with HR (95%CI) of 1.303 (1.065, 1.595) and 1.265 (1.040, 1.539), respectively. Subgroup analysis suggested that in more severe cancer patients, the worse outcome related to INHA might be more significant. Conclusion This retrospective analysis identifies that TIVA is associated with better outcomes compared with INHA. Future prospective studies clinical and translational studies are required to verify this difference and investigate underlying pathophysiology.

Abstract Perioperative sleep disturbance is a risk factor for persistent pain after surgery. Clinical studies have shown that patients with insufficient sleep before and after surgery experience more intense and long-lasting postoperative pain. We hypothesize that sleep deprivation alters L-type calcium channels in the dorsal root ganglia (DRG), thus delaying the recovery from post-surgical pain. To verify this hypothesis, and to identify new predictors and therapeutic targets for persistent postoperative pain, we first established a model of postsurgical pain with perioperative sleep deprivation (SD) by administering hind paw plantar incision to sleep deprivation rats. Then we conducted behavioral tests, including tests with von Frey filaments and a laser heat test, to verify sensory pain, measured the expression of L-type calcium channels using western blotting and immunofluorescence of dorsal root ganglia (an important neural target for peripheral nociception), and examined the activity of L-type calcium channels and neuron excitability using electrophysiological measurements. We validated the findings by performing intraperitoneal injections of calcium channel blockers and microinjections of dorsal root ganglion cells with adeno-associated virus. We found that short-term sleep deprivation before and after surgery increased expression and activity of L-type calcium channels in the lumbar dorsal root ganglia, and delayed recovery from postsurgical pain. Blocking these channels reduced impact of sleep deprivation. We conclude that the increased expression and activity of L-type calcium channels is associated with the sleep deprivation-mediated prolongation of postoperative pain. L-type calcium channels are thus a potential target for management of postoperative pain.

Globally, about two million people die from liver diseases every year. Liver transplantation is the only reliable therapy for severe end-stage liver disease, however, the shortage of organ donors is a huge limitation. Human hepatocytes derived liver progenitor-like cells (HepLPCs) have been reported as a novel source of liver cells for development of in vitro models, cell therapies, and tissue-engineering applications, but their functionality as transplantation donors is unclear. Here, a 3-dimensional (3D) co-culture system using HepLPCs and human umbilical vein endothelial cells (HUVECs) was developed. These HepLPC spheroids mimicked the cellular interactions and architecture of mature hepatocytes, as confirmed through ultrastructure morphology, gene expression profile and functional assays. HepLPCs encapsulated in alginate beads are able to mitigate liver injury in mice treated with carbon tetrachloride (CCL4), while alginate coating protects the cells from immune attack. We confirmed these phenomena due to HUVECs producing glial cell line-derived neurotrophic factor (GDNF) to promote HepLPCs maturation and enhance HepLPCs tight junction through MET phosphorylation. Our results display the efficacy and safety of the alginate microencapsulated spheroids in animal model with acute liver injury (ALF), which may suggest a new strategy for cell therapy.

Numerous studies have demonstrated the impaired cardiovascular reactivity in cholestasis patients and bile duct ligated animals. However, the underlying mechanism remains uncertain. Transient receptor potential cation V4 (TRPV4) channels are reported to be naturally expressed in the cardiovascular system, especially on endothelial cells. However, the role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular reactivity is poorly established. In this study, we first determined that bile acids elicited endothelium-dependent vasoconstrictor hypo-activity via TRPV4 channels, which further activated cyclooxygenase 2 (COX2). Myography results demonstrated that the vascular contractile response was attenuated in BDL rats when exposed to 60 mmol/L KCl. Real time PCR and western blotting results showed that bile duct ligation (BDL) induced a time-dependent increase in TRPV4 expression levels. In addition, bile acids upregulated the expression of TRPV4 protein, which proved to be located on the cell surface of endothelial cells, and induced intracellular Ca2+ events. The relaxation response was increased while the contractile response was decreased in BDL rats, and those effects were reversed by a TRPV4 inhibitor (HC067047). Contractions induced by norepinephrine were primarily inhibited by the COX2 inhibitor, but not the NOS inhibitor, and the expression of COX2 was downregulated after TRPV4 inhibition. These data indicated that TRPV4/COX2 pathways in the endothelium are involved in vasoconstrictor hypo-activity. Our current results suggested that the TRPV4 pathway is involved in the regulation of bile acids in vasoconstrictor hypo-activity in bile duct ligation rats.

Norepinephrine (NE) is often administered during the perioperative period of liver transplantation to address hemodynamic instability and to improve organ perfusion and oxygen supply. However, its role and safety profile have yet to be evaluated in pediatric living donor liver transplantation (LDLT). We hypothesized that intraoperative NE infusion might affect pediatric LDLT outcomes. A retrospective study of 430 pediatric patients (median [interquartile range] age, 7 [6.10] months; 189 [43.9%] female) receiving LDLT between 2014 and 2016 at Renji Hospital was conducted. We evaluated patient survival among recipients who received intraoperative NE infusion (NE group, 85 recipients) and those that did not (non-NE group, 345 recipients). The number of children aged over 24 months and weighing more than 10 kg in NE group was more than that in non-NE group. And children in NE group had longer operative time, longer anhepatic phase time and more fluid infusion. After multivariate regression analysis and propensity score regression adjusting for confounding factors to determine the influence of intraoperative NE infusion on patient survival, the NE group had a 169% more probability of dying. Although there was no difference in mean arterial pressure changes relative to the baseline between the two groups, we did observe increased heart rates in NE group compared with those of the non-NE group at anhepatic phase (P=0.025), neohepatic phase (P=0.012) and operation end phase (P=0.017) of the operation. In conclusion, intraoperative NE infusion was associated with a poorer prognosis for pediatric LDLT recipients. Therefore, we recommend the application of NE during pediatric LDLT should be carefully re-considered.

Patients with obstructive jaundice are prone to develop cardiovascular complications during surgery. However, the underlying mechanisms remain largely unknown. The present study was aimed to investigate the role of p38 MAPK-pHsp27 pathway in vascular hyporesponsiveness induced by obstructive jaundice. Firstly, an experimental rat obstructive jaundice model was established by bile duct ligation (BDL). We found that the thoracic aorta rings isolated from BDL rats showed decreased response to norepinephrine and acetylcholine, while continuous intraperitoneal injection with SB203580, a selective P38 MAPK inhibitor, could significantly prevented BDL-induced hyporeactivity. Also, the immunohistochemistry and Western blot assays revealed that the up-regulation of pHsp27 and F-actin in thoracic aorta rings from BDL rats and bilirubin-treated vascular smooth muscle cells (VSMCs) were also inhibited by SB203580. Moreover, we identified that bilirubin could induced decreased cell proliferation of VSMCs by using CCK8 assay and which was also prevented by SB203580. All these data demonstrated that p38 MAPK-pHsp27 mediates vascular hyporesponsiveness in rats with obstructive jaundice by modulating the expression level of pHsp27 and F-actin, and that inhibition of p38 MAPK signaling could remodel the vascular activity.

An optimal therapeutics to manage opioid withdrawal syndrome is desired for opioid addiction treatment. Down-regulation of endogenous endomorphin-2 (EM2) level in the central nervous system after continuous morphine exposure was observed, which suggested that increase of EM2 could be an alternative novel method for opioid dependence. As a short peptide, the short half-life of EM2 limits its clinical usage through conventional administration. In the present study, we engineered an EM2 gene using a signal peptide of mouse growth factor for an out-secretory expression of EM2 and an adenovirus as a vector, which ultimately sustained the release of EM-2. After administration of the adenovirus in central nervous system, a sustained increase of EM2 level in the cerebral spinal fluid (CSF) was observed along with a reduction of morphine withdrawal syndrome. These findings suggest that the engineered EM2 gene delivered to the central nervous system could be a novel therapeutics for withdrawal syndrome in opioid dependent subjects.

BACKGROUND: Reactive oxygen and nitrogen species are key molecules that mediate neuropathic pain. Although hydrogen is an established antioxidant, its effect on chronic pain has not been characterized. This study was to investigate the efficacy and mechanisms of hydrogen-rich normal saline induced analgesia. METHODOLOGY/PRINCIPAL FINDINGS: In a rat model of neuropathic pain induced by L5 spinal nerve ligation (L5 SNL), intrathecal injection of hydrogen-rich normal saline relieved L5 SNL-induced mechanical allodynia and thermal hyperalgesia. Importantly, repeated administration of hydrogen-rich normal saline did not lead to tolerance. Preemptive treatment with hydrogen-rich normal saline prevented development of neuropathic pain behavior. Immunofluorochrome analysis revealed that hydrogen-rich normal saline treatment significantly attenuated L5 SNL-induced increase of 8-hydroxyguanosine immunoreactive cells in the ipsilateral spinal dorsal horn. Western blot analysis of SDS/PAGE-fractionated tyrosine-nitrated proteins showed that L5 SNL led to increased expression of tyrosine-nitrated Mn-containing superoxide dismutase (MnSOD) in the spinal cord, and hydrogen-rich normal saline administration reversed the tyrosine-nitrated MnSOD overexpression. We also showed that the analgesic effect of hydrogen-rich normal saline was associated with decreased activation of astrocytes and microglia, attenuated expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord. CONCLUSION/SIGNIFICANCE: Intrathecal injection of hydrogen-rich normal saline produced analgesic effect in neuropathic rat. Hydrogen-rich normal saline-induced analgesia in neuropathic rats is mediated by reducing the activation of spinal astrocytes and microglia, which is induced by overproduction of hydroxyl and peroxynitrite.

BACKGROUND: The practice of giving certain authors equal credit in original research publications was increasingly common in some specialty. This study aimed to investigate the prevalence and characteristics of designating some authors with equally credited authors (ECAs) in major anaesthesia journals. METHODOLOGY/PRINCIPAL FINDINGS: The practice of giving authors equal credit was searched and identified in the three major anaesthesia journals between January 1, 2002 and December 31, 2011. Papers with ECAs had a higher proportion of the total number of articles in 2011 versus published in 2002 (Anesthesiology, 8.8% vs. 0.9%; British Journal of Anaesthesia, 8.8% vs. 0%; Anesthesia & Analgesia, 3.4% vs. 0.3%; totally, 6.4% vs. 0.4%). A significant increasing trend in annual proportion of articles with ECA was found in the three journals. The first two authors listed in the byline had equal credit in most cases. CONCLUSIONS/SIGNIFICANCE: The practice of giving authors equal credit in original research papers is increasingly common in major anaesthesia journals. It may be warranted for the journals to guide the authors how to regard this practice.

BACKGROUND:Anesthetics are variable in patients with obstructive jaundice. The minimum alveolar concentration awake of desflurane is reduced in patients with obstructive jaundice, while it has no effect on pharmacodynamics and pharmacokinetics of propofol. In this study, we investigated the influence of obstructive jaundice on the pharmacodynamics and blood concentration of rocuronium. METHODS:Included in this study were 26 control patients and 27 patients with obstructive jaundice. Neuromuscular block of rocuronium was monitored by acceleromyography. Onset time, spontaneous recovery of the height of twitch first (T1) to 25% of the final T1 value (Duration 25%, Dur 25%), recovery index (RI), and spontaneous recovery of train-of-four (TOF) ratios to 70% were measured. The plasma rocuronium concentrations were determined by high performance liquid chromatography using berberine as an internal standard. RESULTS:There was no significant difference in onset time between the two groups. The Dur 25%, the recovery index and the time of recovery of the TOF ratios to 70% were all prolonged in the obstructive jaundice group compared with the control group. The plasma concentration of rocuronium at 60, 90 and 120 min after bolus administration was significantly higher in the obstructive jaundice group. CONCLUSIONS:The neuromuscular blockade by rocuronium is prolonged in obstructive jaundice patients, and therefore precautions should be taken in case of postoperative residual neuromuscular block. The possible reason is impedance of rocuronium excretion due to biliary obstruction and increased plasma unbound rocuronium because of free bilirubin competing with it for albumin binding.

BACKGROUND:The PRISMA (Preferred Reporting Items of Systematic reviews and Meta-Analyses) Statement was published to help authors improve how they report systematic reviews. It is unknown how many journals mention PRISMA in their instructions to authors, or whether stronger journal language regarding use of PRISMA improves author compliance. METHODOLOGY/PRINCIPAL FINDINGS:An Internet-based investigation examined the extent to which 146 leading medical journals have incorporated the PRISMA Statement into their instructions to authors. Results were analyzed using descriptive statistics. Also, systematic reviews published in the leading anesthesiology journals and the QUOROM (QUality Of Reporting Of Meta-analyses) Statement were used to explore the hypothesis that indicating compliance with the QUOROM Statement in the manuscript is associated with improved compliance with the reporting guideline. In a sample of 146 journals publishing systematic reviews, the PRISMA Statement was referred to in the instructions to authors for 27% (40/146) of journals; more often in general and internal medicine journals (7/14; 50%) than in specialty medicine journals (33/132; 25%). In the second part of the study, 13 systematic reviews published in the leading anesthesiology journals in 2008 were included for appraisal. Mention of the QUOROM Statement in the manuscript was associated with higher compliance with the QUOROM checklist (P = 0.022). CONCLUSIONS/SIGNIFICANCE:Most of the leading medical journals used ambiguous language regarding what was expected of authors. Further improvement on quality of reporting of systematic reviews may entail journals clearly informing authors of their requirements. Stronger directions, such as requiring an indication of adherence to a research quality of reporting statement in the manuscript, may improve reporting and utility of systematic reviews.

Abstract Metronidazole in aqueous solution is sensitive to light and UV irradiation, leading to the formation of N-(2-hydroxyethyl)-5-methyl-l,2,4-oxadiazole-3-carboxamide. This is revealed here by liquid chromatography with tandem photo diode array detection and mass spectrometry (LC-PDA-MS) and further verified by comparison with the corresponding reference substance and proton nuclear magnetic resonance (1H-NMR). However, in current compendial tests for related substances/organic impurities of metronidazole, the above photolytic degradant could not be detected. Thus, when photodegradation of metronidazole occurs, it could not be demonstrated. In our study, an improved LC method was developed and validated, which includes a detection at a wavelength of 230 nm and optimization of mobile phase composition thereby a better separation was obtained.

Recent studies suggest that a variety of medical gases confer neuroprotective effects against cerebral ischemia, extending function beyond their regular clinical applications. The mechanisms underlying ischemic neuroprotection afforded by medical gases have been intensively studied over the past two decades. A number of signaling pathways have been proposed, among which anti-inflammatory signaling has been proven to be critical. Pursuit of the role for anti-inflammatory signaling may shed new light on the translational application of medical gas-afforded neuroprotection. [ABSTRACT FROM AUTHOR]

After primary dissemination of Mycobacterium tuberculosis bacillus infection that is localized in liver, disease progression and changes to immune function in the body occur. Various forms of tuberculosis, including granuloma, caseous necrosis, liquefactive necrosis, fibrosis, and calcification, occur that could be presented at different stages, and imaging examination shows findings that are consistent with these stages. Not all liver tuberculosis patients are suitable for liver resection, and preoperative imaging examination and pathological immunohistochemical results could be used to determine whether tuberculosis was active, avoid unnecessary liver resection, and prevent the postoperative spread of tuberculosis. Here, we reported a case of miliary tuberculosis, pelvic tuberculosis, and tuberculous abscess of the thigh muscle in a 51-year-old man after liver lesion resection. The liver lesion was confirmed to be tuberculosis by surgical pathology, which is rare and has not been previously reported. The purpose of this case report is to remind radiologists of the importance of the floral-like enhancement and to estimate whether liver tuberculosis is active. This will help to guide clinicians to determine the timing of surgery, avoid unnecessary liver resection, and avoid hematogenous transmission.

Background: Rapid and effective treatment of cancer-induced bone pain remains a clinical challenge and patients with bone metastasis are more likely to experience severe pain. The voltage-gated sodium channel Nav1.8 plays a critical role in many aspects of nociceptor function. Therefore, we characterized a rat model of cancer pain and investigated the potential role of Nav1.8. Methods: Adult female Wistar rats were used for the study. Cancer pain was induced by inoculation of Walker 256 breast carcinosarcoma cells into the tibia. After surgery, mechanical and thermal hyperalgesia and ambulation scores were evaluated to identify pain-related behavior. We used real-time RT-PCR to determine Nav1.8 mRNA expression in bilateral L4/L5 dorsal root ganglia (DRG) at 16-19 days after surgery. Western blotting and immunofluorescence were used to compare the expression and distribution of Nav1.8 in L4/L5 DRG between tumor-bearing and sham rats. Antisense oligodeoxynucleotides (ODNs) against Nav1.8 were administered intrathecally at 14-16 days after surgery to knock down Nav1.8 protein expression and changes in pain-related behavior were observed. Results: Tumor-bearing rats exhibited mechanical hyperalgesia and ambulatory-evoked pain from day 7 after inoculation of Walker 256 cells. In the advanced stage of cancer pain (days 16-19 after surgery), normalized Nav1.8 mRNA levels assessed by real-time RT-PCR were significantly lower in ipsilateral L4/L5 DRG of tumor-bearing rats compared with the sham group. Western-blot showed that the total expression of Nav1.8 protein significantly decreased bilaterally in DRG of tumor-bearing rats. Furthermore, as revealed by immunofluorescence, only the expression of Nav1.8 protein in small neurons down regulated significantly in bilateral DRG of cancer pain rats. After administration of antisense ODNs against Nav1.8, Nav1.8 protein expression decreased significantly and tumor-bearing rats showed alleviated mechanical hyperalgesia and ambulatory-evoked pain. Conclusions: These findings suggest that Nav1.8 plays a role in the development and maintenance of bone cancer pain. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of low central venous pressure (LCVP) on blood loss and blood transfusion in patients undergoing hepatectomy., Methods: Electronic databases and bibliography lists were searched for potential articles. A meta-analysis of all randomized controlled trials (RCTs) investigating LCVP in hepatectomy was performed. The following three outcomes were analyzed: blood loss, blood transfusion and duration of operation., Results: Five RCTs including 283 patients were assessed. Meta-analysis showed that blood loss in the LCVP group was significantly less than that in the control group (MD = -391.95, 95%CI: -559.35--224.56, P < 0.00001). In addition, blood transfusion in the LCVP group was also significantly less than that in the control group (MD = -246.87, 95%CI: -427.06--66.69, P = 0.007). The duration of operation in the LCVP group was significantly shorter than that in the control group (MD = -18.89, 95%CI: -35.18--2.59, P = 0.02). Most studies found no significant difference in renal and liver function between the two groups., Conclusion: Controlled LCVP is a simple and effective technique to reduce blood loss and blood transfusion during liver resection, and appears to have no detrimental effects on liver and renal function.