Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver Failure.

BACKGROUND & AIMS: HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a multicellular etiology. METHODS: Progressive changes in the rat carbon tetrachloride model were studied by deep RNA sequencing and genome-wide chromatin immunoprecipitation sequencing analysis of transcription factor (TF) binding and chromatin modification. Studies compared decompensated cirrhosis with liver failure after 26 weeks of treatment with earlier compensated cirrhosis and with additional rat models of chronic fibrosis. Finally, to resolve cell-specific responses and intercellular signaling, we compared transcriptomes of liver, nonparenchymal, and inflammatory cells. RESULTS: HNF4α was significantly lower in 26-week cirrhosis, part of a general reduction of TFs that regulate metabolism. Nevertheless, increased binding of HNF4α contributed to strong activation of major phenotypic genes, whereas reduced binding to other genes had a moderate phenotypic effect. Decreased Hnf4a expression was the combined effect of STAT3 and nuclear factor kappa B (NFκB) activation, which similarly reduced expression of other metabolic TFs. STAT/NFκB also induced de novo expression of Osmr by hepatocytes to complement induced expression of Osm by nonparenchymal cells. CONCLUSIONS: Liver decompensation by inflammatory STAT3 and NFκB signaling was not a direct consequence of progressive cirrhosis. Despite significant reduction of Hnf4a expression, residual levels of this abundant TF still stimulated strong new gene expression. Reduction of HNF4α was part of a broad hepatocyte transcriptional response to inflammation.

Application of remimazolam transversus abdominis plane block in gastrointestinal tumor surgery.

BACKGROUND: Transversus abdominis plane block (TAPB) is a block of the abdominal afferent nerve fibers between the internal oblique muscle and the transverse abdominal muscle achieved with local anesthetics. It can effectively block the conduction of the anterior nerve of the abdominal wall and exert a good analgesic effect. However, the effect of combining the block with remimazolam on anesthesia in patients undergoing gastrointestinal tumor surgery is still unclear. AIM: To examine the effects of combining TAPB with remimazolam on the stress response and postoperative recovery of gastrointestinal tumor surgery patients. METHODS: A retrospective analysis was conducted on the clinical data of 102 individuals diagnosed with gastrointestinal malignancies who underwent laparoscopic surgery under general anesthesia between April 2020 and June 2023. The patients were categorized into a control group (n = 51), receiving remimazolam for general anesthesia, and an observation group (n = 51), receiving TAPB combined with remimazolam for general anesthesia. A comparison was made between both groups in terms of hemodynamic parameters, stress markers, pain levels, recovery quality, analgesic effects, and adverse reactions during the perioperative period. RESULTS: The observation group had significantly higher heart rates at time points 1 min after induction and upon leaving the operating room than the control group (P < 0.05). The mean arterial pressure at time point T1 in the observation group was significantly higher than that in the control group (P < 0.05). Five minutes after extubation, the levels of the hormones adrenaline and noradrenaline in the observation group were considerably lower than those in the control group (P < 0.05). At 12 h, 24 h, and 48 h following surgery, the visual analog scale scores of the observation group were considerably lower than those of the control group (P < 0.05). The observation group had shorter awakening and extubation times and lower Riker sedation-agitation scale scores than the control group (P < 0.05). The observation group exhibited considerably fewer effective pump presses, lower fentanyl dosages, and lower incidences of rescue analgesia within 24 h following surgery than the control group (P < 0.05). CONCLUSION: The application effect of TAPB combined with remimazolam general anesthesia in anesthesia of patients undergoing gastrointestinal tumor surgery is good, which is helpful to promote faster recovery after operation.

Gadd45 in the Liver: Signal Transduction and Transcriptional Mechanisms.

Injury and growth stimulation both remarkably increase the hepatic expression of Gadd45ß. This contrasts with expression in liver cancer, where promoter methylation frequently silences Gadd45ß, due to a suppressive function that is often proapoptotic. In normal hepatocytes, Gadd45ß facilitates cell survival, growth, and proliferation. Gadd45ß binds MKK7-downstream of TNFα and its receptors-to prevent this kinase from activating JNK2. Hence, the Gadd45ß-/- genotype increases cell injury and decreases cell proliferation during liver regeneration (compensatory growth and proliferation). Liver hyperplasia (de novo growth and proliferation) is an alternate form of growth, caused by drugs that activate the nuclear receptor, CAR. As in regeneration, the Gadd45ß-/- genotype considerably slows growth during hyperplasia. However, there is no injury and the slowing occurs because Gadd45ß normally binds to CAR and activates its transcriptional stimulation. Thus, Gadd45ß protects the liver through two entirely different processes: Binding MKK7 to block damaging signal transduction, or binding CAR to coactivate anabolic transcription.

Nkx2.9 Contributes to Mid-Hindbrain Patterning by Regulation of mdDA Neuronal Cell-Fate and Repression of a Hindbrain-Specific Cell-Fate.

Nkx2.9 is a member of the NK homeobox family and resembles Nkx2.2 both in homology and expression pattern. However, while Nkx2.2 is required for development of serotonergic neurons, the role of Nkx2.9 in the mid-hindbrain region is still ill-defined. We have previously shown that Nkx2.9 expression is downregulated upon loss of En1 during development. Here, we determined whether mdDA neurons require Nkx2.9 during their development. We show that Nkx2.9 is strongly expressed in the IsO and in the VZ and SVZ of the embryonic midbrain, and the majority of mdDA neurons expressed Nkx2.9 during their development. Although the expression of Dat and Cck are slightly affected during development, the overall development and cytoarchitecture of TH-expressing neurons is not affected in the adult Nkx2.9-depleted midbrain. Transcriptome analysis at E14.5 indicated that genes involved in mid- and hindbrain development are affected by Nkx2.9-ablation, such as Wnt8b and Tph2. Although the expression of Tph2 extends more rostral into the isthmic area in the Nkx2.9 mutants, the establishment of the IsO is not affected. Taken together, these data point to a minor role for Nkx2.9 in mid-hindbrain patterning by repressing a hindbrain-specific cell-fate in the IsO and by subtle regulation of mdDA neuronal subset specification.

Sevoflurane alleviates LPS­induced acute lung injury via the microRNA­27a­3p/TLR4/MyD88/NF­κB signaling pathway.

Acute lung injury (ALI) is a critical syndrome that is associated with a high morbidity and mortality in patients. Sevoflurane has a lung protective effect in ALI as it reportedly has anti­inflammatory and apoptotic­regulating activity. However, the mechanism is still not entirely understood. The aim of the present study was to explore the effects of sevoflurane on lipopolysaccharide (LPS)­induced ALI in mice and the possible mechanisms involved. The results revealed that sevoflurane treatment improved LPS­induced lung injury, as evidenced by the reduction in mortality, lung permeability, lung wet/dry ratio and lung histopathological changes in mice. Total cell counts and the production of pro­inflammatory cytokines [tumor necrosis factor­α, interleukin (IL)­1ß and IL­6] in bronchoalveolar fluid were also decreased following treatment with sevoflurane. Additionally, LPS­triggered apoptosis in lung tissues, which was eliminated by sevoflurane. Furthermore, a miRCURY™ LNA array was employed to screen for differentially expressed microRNAs (miRs/miRNAs). Among these miRNAs, 6 were differentially expressed and were involved in the inflammatory response, but only miR­27a­3p (miR­27a) was regulated by sevoflurane. Subsequently, the present study investigated whether sevoflurane exerts its function through the modulation of miR­27a. The results demonstrated that the overexpression of miR­27a via an injection with agomiR­27a produced similar protections as sevoflurane, while the inhibition of miR­27a suppressed the lung protective effects of sevoflurane in ALI mice. In addition, the present study identified that miR­27a inhibited Toll­like receptor 4 (TLR4) by binding to its 3'­untranslated region. Western blot analysis demonstrated that sevoflurane may ameliorate the inflammatory response by blocking the miR­27a/TLR4/MyD88/NF­κB signaling pathway. The present results indicate that sevoflurane may be a viable therapeutic option in the treatment of patients with ALI.

Retraction Note: Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors.

This paper has been retracted.

Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8.

BACKGROUND & AIMS: Upon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about the mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms. METHODS: We used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration. We analyzed zebrafish with disruptions of the histone deacetylase 1 gene (hdac1) or exposed to MS-275 (an inhibitor of Hdac1, Hdac2, and Hdac3). We also analyzed zebrafish with mutations in sox9b, fbxw7, kdm1a, and notch3. Zebrafish larvae were collected and analyzed by whole-mount immunostaining and in situ hybridization; their liver tissues were collected for quantitative reverse transcription polymerase chain reaction. We studied mice in which hepatocyte-specific deletion of ß-catenin (Ctnnb1flox/flox mice injected with Adeno-associated virus serotype 8 [AAV8]-TBG-Cre) induces differentiation of LPCs into hepatocytes after a choline-deficient, ethionine-supplemented (CDE) diet. Liver tissues were collected and analyzed by immunohistochemistry and immunoblots. We performed immunohistochemical analyses of liver tissues from patients with compensated or decompensated cirrhosis or acute on chronic liver failure (n = 15). RESULTS: Loss of Hdac1 activity in zebrafish blocked differentiation of LPCs into hepatocytes by increasing levels of sox9b mRNA and reduced differentiation of LPCs into BECs by increasing levels of cdk8 mRNA, which encodes a negative regulator gene of Notch signaling. We identified Notch3 as the receptor that regulates differentiation of LPCs into BECs. Loss of activity of Kdm1a, a lysine demethylase that forms repressive complexes with Hdac1, produced the same defects in differentiation of LPCs into hepatocytes and BECs as observed in zebrafish with loss of Hdac1 activity. Administration of MS-275 to mice with hepatocyte-specific loss of ß-catenin impaired differentiation of LPCs into hepatocytes after the CDE diet. HDAC1 was expressed in reactive ducts and hepatocyte buds of liver tissues from patients with cirrhosis. CONCLUSIONS: Hdac1 regulates differentiation of LPCs into hepatocytes via Sox9b and differentiation of LPCs into BECs via Cdk8, Fbxw7, and Notch3 in zebrafish with severe hepatocyte loss. HDAC1 activity was also required for differentiation of LPCs into hepatocytes in mice with liver injury after the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases.

Constitutive Activation of the Human Aryl Hydrocarbon Receptor in Mice Promotes Hepatocarcinogenesis Independent of Its Coactivator Gadd45b.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared with the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 ß (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis.

Binding of Drug-Activated CAR/Nr1i3 Alters Metabolic Regulation in the Liver.

The constitutive androstane receptor (CAR/Nr1i3) regulates detoxification of drugs and other xenobiotics by the liver. Binding of these compounds, activating ligands, causes CAR to translocate to the nucleus and stimulate genes of detoxification. However, CAR activation also changes metabolism and induces rapid liver growth. To explain this gene regulation, we characterized the genome-wide early binding of CAR; its binding partner, RXRα; and the acetylation that they induced on H4K5. CAR-linked genes showed either stimulation or inhibition and regulated lipid, carbohydrate, and energy metabolism, as well as detoxification. Stimulation of expression increased, but inhibition did not decrease, H4K5Ac. Transcriptional inhibition occurred when CAR bound with HNF4α, PPARα, or FXR on the same enhancers. Functional competition among these bound nuclear receptors normally coordinates transcriptional resources as metabolism shifts. However, binding of drug-activated CAR to the same enhancers adds a new competitor that constitutively alters the normal balance of metabolic gene regulation.

ß-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis.

Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/ß-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific ß-catenin knockout mice and wild-type littermates were subjected to cholestatic injury through bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Intriguingly, knockout mice exhibit a dramatic protection from liver injury, fibrosis, and atypical ductular proliferation, which coincides with significantly decreased total hepatic bile acids (BAs). This led to the discovery of a role for ß-catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that ß-catenin functions as both an inhibitor of nuclear translocation and a nuclear corepressor through formation of a physical complex with FXR. Loss of ß-catenin expedited FXR nuclear localization and FXR/retinoic X receptor alpha association, culminating in small heterodimer protein promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of ß-catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of ß-catenin expression during cholestatic injury reduces ß-catenin/FXR complex activation of FXR to decrease total BA and alleviate hepatic injury. CONCLUSION: We have identified an FXR/ß-catenin interaction whose modulation through ß-catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (Hepatology 2018;67:955-971).

Anesthetic isoflurane attenuates activated microglial cytokine-induced VSC4.1 motoneuronal apoptosis.

Isoflurane (ISO) exhibits neuroprotective effects against inflammation and apoptosis. However, the role of ISO in motoneuronal apoptosis induced by activated microglia remains poorly studied. We investigated the protective effects of ISO on the apoptosis of ventral spinal cord 4.1 (VSC4.1) motoneurons induced by lipopolysaccharide (LPS)-activated BV-2 microglia. Results indicated that ISO inhibited NF-κB activation and pro-inflammatory cytokine release in LPS-treated BV-2 microglia. Conditioned medium (CM) from activated BV-2 cells treated by ISO directly prevented VSC4.1 motoneurons from LPS-CM-induced neuronal apoptosis, as determined by the following: reductions in caspase-8, caspase-9, and caspase-3 activities; downregulation of pro-apoptotic procaspase-8, cleaved (cl)-caspase-8, procaspase-9, cl-caspase-9, caspase-3, cl-caspase-3, Bid, Bax, and cytochrome c expression; and upregulation of anti-apoptotic Bcl-2 expression in LPS-CM-cultured VSC4.1 motoneurons. Findings demonstrated that ISO inhibits BV-2 microglia activation and alleviates VSC4.1 motoneuronal apoptosis induced by microglial activation. These effects suggest that ISO can be used as an alternative agent for reducing neuronal apoptosis.

Precise let-7 expression levels balance organ regeneration against tumor suppression.

The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.

Is single-operator peroral cholangioscopy a useful tool for the diagnosis of indeterminate biliary lesion? A systematic review and meta-analysis.

BACKGROUND: Differentiating between malignant and benign biliary lesions is critical in clinical practice but is difficult. OBJECTIVE: To systematically evaluate the diagnostic performance of single-operator peroral cholangioscopy on indeterminate biliary lesions. DESIGN: A systematic review and meta-analysis. PATIENTS: Patients with indeterminate biliary lesions or equivocal ERCP findings. MAIN OUTCOME MEASUREMENTS: The diagnostic performance of single-operator peroral cholangioscopy on indeterminate biliary lesions. The area under the summary receiver-operating characteristic curve was used as the main indicator for the overall diagnostic performance of single-operator peroral cholangioscopy visual impression (VI) and SpyBite biopsy (SB). The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were also synthesized. RESULTS: A total of 8 studies met the inclusion criteria, involving 335 patients who had data on VI and 337 who had data on SB. The area under the curve values on the summary receiver-operating characteristic curve of single-operator peroral cholangioscopy VI and SB were 0.94 (95% confidence interval [CI], 0.92-0.96) and 0.93 (95% CI, 0.90-0.95) respectively. The combined sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 90% (95% CI, 73%-97%), 87% (95% CI, 76%-94%), 7.1 (95% CI, 3.8-13.3), 0.12 (95% CI, 0.04-0.33) for VI and 69% (95% CI, 57%-79%), 98% (95% CI, 92%-99%), 30.1 (95% CI, 8.5-106.9), and 0.32 (95% CI, 0.23-0.44) for SB, respectively. LIMITATIONS: Small number of included studies; comparison with ERCP could not be made. CONCLUSION: Single-operator peroral cholangioscopy is a good tool for differentiating malignant and benign biliary lesions. VI is useful for detecting malignant lesion, whereas SB is better at confirming a malignant diagnosis, but VI is not perfect in excluding biliary cancer, nor is SB, and their negative results should be interpreted with caution.

Resetting the transcription factor network reverses terminal chronic hepatic failure.

The cause of organ failure is enigmatic for many degenerative diseases, including end-stage liver disease. Here, using a CCl4-induced rat model of irreversible and fatal hepatic failure, which also exhibits terminal changes in the extracellular matrix, we demonstrated that chronic injury stably reprograms the critical balance of transcription factors and that diseased and dedifferentiated cells can be returned to normal function by re-expression of critical transcription factors, a process similar to the type of reprogramming that induces somatic cells to become pluripotent or to change their cell lineage. Forced re-expression of the transcription factor HNF4α induced expression of the other hepatocyte-expressed transcription factors; restored functionality in terminally diseased hepatocytes isolated from CCl4-treated rats; and rapidly reversed fatal liver failure in CCl4-treated animals by restoring diseased hepatocytes rather than replacing them with new hepatocytes or stem cells. Together, the results of our study indicate that disruption of the transcription factor network and cellular dedifferentiation likely mediate terminal liver failure and suggest reinstatement of this network has therapeutic potential for correcting organ failure without cell replacement.

Role of miR-34c in ketamine-induced neurotoxicity in neonatal mice hippocampus.

Ketamine is a commonly used pediatric anesthetic, but it might affect development, or even induce neurotoxicity in the neonatal brain. We have used an in vivo neonatal mouse model to induce ketamine-related neurotoxicity in the hippocampus, and found that miR-34c, a microRNA associated with pathogenesis of Alzheimer's disease, was significantly upregulated during ketamine-induced hippocampal neurodegeneration. Functional assay of silencing miR-34c demonstrated that downregulation of miR-34c activated PKC-ERK pathway, upregulated anti-apoptotic protein BCL2, and ameliorated ketamine-induced apoptosis in the hippocampus. Cognitive examination with the Morris water maze test showed that ketamine-induced memory impairment was significantly improved by miR-34c downregulation. Thus, miR-34c is important in regulating ketamine-induced neurotoxicity in hippocampus.

Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors.

Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05-0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain.

Gadd45 in the liver: signal transduction and transcriptional mechanisms.

Injury and growth stimulation both remarkably increase the hepatic expression of Gadd45ß. In liver cancer, promoter methylation frequently silences Gadd45ß, demonstrating due to a suppressive function that is often proapoptotic. This contrasts with normal hepatocytes, where Gadd45ß facilitates cell survival, growth, and proliferation. Gadd45ß binds MKK7-downstream of TNFα and its receptors-to prevent this kinase from activating JNK2. Hence, the Gadd45b-/- genotype increases cell injury and decreases cell proliferation during liver regeneration (i.e., compensatory growth and proliferation). Liver hyperplasia (i.e., de novo growth and proliferation) is an alternate form of growth, caused by drugs that activate the nuclear receptor, CAR. As in regeneration, the Gadd45b-/- genotype considerably slows growth during hyperplasia. However, there is no injury and the slowing occurs because Gadd45ß normally binds to CAR and activates its transcriptional stimulation. Thus, Gadd45ß protects the liver through two entirely different processes: binding MKK7 to block damaging signal transduction or binding CAR to coactivate anabolic transcription.

Metabolic syndrome as a risk factor for Barrett esophagus: a population-based case-control study.

OBJECTIVES: To assess the association between Barrett esophagus (BE) and the metabolic syndrome in patients with and without reflux symptoms and to determine whether this association is reflux independent and metabolically driven. PATIENTS AND METHODS: Case patients with BE and controls were residents of Olmsted County, Minnesota (1999-2006). Two control groups (one with and one without symptoms of gastroesophageal reflux) were identified from a cohort of patients who had responded to a validated gastrointestinal symptom questionnaire. Cases and controls were individually matched by age, sex, and duration of follow-up. Controls did not have a known diagnosis of BE. The association of the metabolic syndrome and its individual components with BE was assessed using univariate and multivariate conditional logistic regression separately for each control group. RESULTS: A total of 309 patients were included (103 BE cases, 103 controls with reflux symptoms, and 103 controls without reflux symptoms). A total of 64% of cases, 47% of controls with reflux symptoms, and 50% of controls without reflux symptoms had the metabolic syndrome. The metabolic syndrome was associated with a 2-fold increased risk of BE relative to those with (odds ratio, 2.00; 95% CI, 1.10-3.65; P=.02) and without (odds ratio, 1.90; 95% CI, 1.03-3.60; P=.04) reflux symptoms. This association was independent of smoking, alcohol consumption, and body mass index and remained robust with sensitivity analysis. CONCLUSION: The metabolic syndrome is associated with BE independent of reflux symptoms, which may reflect a reflux-independent pathway of BE pathogenesis.

Utility of baseline positron emission tomography with computed tomography for predicting endoscopic resectability and survival outcomes in patients with early esophageal adenocarcinoma.

BACKGROUND AND AIMS: Positron emission tomography with computed tomography (PET/CT) has been used to detect metastasis in the diagnosis of esophageal adenocarcinoma (EAC). However, the utility of PET/CT to assess primary tumor for endoscopic resectability and prognosis in early EAC remains unclear. We conducted a retrospective study to determine the association of PET/CT findings with histopathological tumor invasion depth and survival outcomes. METHODS: EAC patients who underwent PET/CT followed by endoscopic mucosal resection (EMR) were included. Pathology on EMR and survival outcomes from a prospectively maintained database was retrieved. Two radiologists independently reviewed the PET/CT using the following parameters: detection of malignancy, fluorodeoxyglucose (FDG) uptake intensity, FDG focality, FDG eccentricity, esophageal thickness, maximal standard uptake value (SUVmax), and SUVmax ratio (lesion/liver). RESULTS: There were 72 eligible patients: 42 (58.3%) had T1a lesions, and 30 (41.7%) had ≥ T1b. Only SUVmax ratio was associated with tumor invasion depth (odds ratio=2.77, 95% confidence interval 1.26-7.73, P=0.0075). Using a cut-off of 1.48, the sensitivity and specificity of SUVmax ratio for identification of T1a lesions were 43.3% and 80.9%, respectively. Adjusting the SUVmax ratio to 2.14, 16.7% (5/30) of ≥ T1b patients were identified without any false-positive cases. Multivariate analysis showed SUVmax ratio, Charlson comorbidity index, and esophagectomy were independent predictors for survival. CONCLUSIONS: SUVmax ratio (lesion/liver) is more accurate in predicting endoscopic resectability and mortality for EAC than other PET/CT parameters and appears promising as a useful adjunct to the current diagnostic work-up.

Preventive effects of sevoflurane treatment on lung inflammation in rats.

OBJECTIVE: To observe the effects of sevoflurane treatment on lung inflammation in rats with lipopoIysaccharide-induced acute lung injury (ALI). METHODS: The rat model of ALI was established by intratracheal instillation of lipopolysaccharide (LPS). 45 infantile SD rats [body weight (272±15) g] were randomly divided into 3 groups (n=15): control group, LPS group, sevoflurane group. NS (1 mL/kg) was instillated in rats' airways of control group; LPS (5 mg/kg) was instillated in rats' airways of LPS group. Sevoflurane group rats received sevoflurane (2.4%) inhalation for a hour after LPS was instillated in rats' airways. Six hours after NS or LPS instillation, all rats were exsanguinated. Lung tissues were examined by HE staining. Expressions of TNF-α and ICAM1 mRNA were detected by semiquantitative RT-PCR techniques. The protein level of TNF-α and ICAM1 were assessed by western blot techniques. RESULTS: In LPS group the permeability of lung tissues increased, organizational structure severely damaged and the alveolar wall tumed thick, with interstitial edema and Europhiles infiltrated increasingly. The LPS group had higher mRNA expressions of TNF-α and ICAM1 than control group and sevoflurane group (P<0.05), and LPS group had higher protein level of TNF-α and ICAM1 than control group and sevoflurane group (P<0.05). CONCLUSIONS: Sevoflurane treatment can attenuate lung inflammation in rats with lipopolysaccharide-induced acute lung injury.