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BACKGROUND Patients with critical coronavirus disease 2019 (COVID-19), characterized by respiratory failure requiring mechanical ventilation (MV), are at high risk of mortality. An effective and practical MV weaning protocol is needed for these fragile cases. CASE SUMMARY Here, we present two critical COVID-19 patients who presented with fever, cough and fatigue. COVID-19 diagnosis was confirmed based on blood cell counts, chest computed tomography (CT) imaging, and nuclei acid test results. To address the patients’ respiratory failure, they first received noninvasive ventilation (NIV). When their condition did not improve after 2 h of NIV, each patient was advanced to MV [tidal volume (Vt), 6 mL/kg ideal body weight (IBW); 8-10 cmH2O of positive end-expiratory pressure; respiratory rate, 20 breaths/min; and 40%-80% FiO2] with prone positioning for 12 h/day for the first 5 d of MV. Extensive infection control measures were conducted to minimize morbidity, and pharmacotherapy consisting of an antiviral, immune-enhancer, and thrombosis prophylactic was administered in both cases. Upon resolution of lung changes evidenced by CT, the patients were sequentially weaned using a weaning screening test, spontaneous breathing test, and airbag leak test. After withdrawal of MV, the patients were transitioned through NIV and high-flow nasal cannula oxygen support. Both patients recovered well. CONCLUSION A MV protocol attentive to intubation/extubation timing, prone positioning early in MV, infection control, and sequential withdrawal of respiratory support, may be an effective regimen for patients with critical COVID-19.

Aim This study investigated whether ischemic postconditioning (IPO) improved the outcome of organs from donors after cardiac death and had a synergistic effect with hypothermic machine perfusion (HMP) in a pig liver transplantation model. Methods A donor after cardiac death (DCD) model was developed in 48 healthy Bama miniature pigs randomly divided into four groups: simple cold storage group (SCS group), IPO group, HMP group, HMP-IPO group. The levels of serum alanine aminotransferase (ALT), total bilirubin, histopathological findings, apoptotic activity of hepatocytes, international normalized ratio (INR), tumor necrosis factor-α (TNF-α), and Malondialdehyde (MDA) were compared. Results All recipients in the SCS group died within 6 h after transplantation. The livers of the recipients in the IPO had 50% survival on day 5. HMP allowed 83.3% survival and HMP-IPO allowed 100% survival. After reperfusion, the recipients in the IPO and HMP-IPO group had lower ALT and total bilirubin levels, less Suzuki score, less apoptosis, and less injury to hepatocytes and biliary ducts and attenuated inflammatory response and oxidative load. Conclusions IPO improved the outcome of organs from donors after cardiac death and had a synergistic effect with HMP in the pig liver transplantation model.

Background We investigated whether the outcome of organs from donors after circulatory death (DCD) can be improved by the addition of mcc950 to the perfusate of the hypothermic machine perfusion (HMP) system and intravenous mcc950 injection after transplantation in a pig liver transplantation model. Methods Thirty-six healthy Bama mini pigs randomized into 3 groups. All the DCD livers were preserved in an HMP system after 2 hours of simple cold storage. In HMP-Postop group, mcc950 was added to the perfusate; in the control group and Postop group, the perfusate was normal LPS. After transplantation, the pigs in the Postop group and HMP-Postop group were intravenously administered 3 mg/kg mcc950, at the time of reperfusion and on day 2 and day 3 after transplantation. During the 3-day follow-up period, general operative characteristics, and serological markers and histological features related to ischemia reperfusion injury were examined. Results The HMP-Postop group suffer the lightest ischemia reperfusion injury (IRI), and functioned best after transplantation. Model for the Early Allograft Function Score (predictor of long-term survival), degree of injury in the hepatocytes and rate of apoptosis was lowest in the HMP-Postop group. Further, in the HMP-Postop group, the nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3 inflammasome pathway activation was lowest, and the level of IL-1β was lowest. Postop group functioned better than control group, but not comparable with HMP-Postop group. Conclusions The outcome of DCD organs can be improved by the addition of mcc950 to the perfusate of the HMP system and intravenous injection of mcc950 after transplantation.

Background Hypothermic machine perfusion (HMP) improves the quality of donor livers for transplantation, both in animal models and in clinical practice. Treatment with SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), can suppress the JNK signaling pathway to alleviate donor liver ischemia–reperfusion injury (IRI). We performed the present study with the objective of exploring the protective effects exerted by a combination of HMP and SP600125 on liver xenograft viability for donation after cardiac death (DCD) in a porcine model. Methods 54 adult BAMA mini-pigs were randomly assigned to 5 groups, including sham, cold storage for 4 h (CS 4 h), CS 4 h + SP600125, CS 2 h + HMP 2 h, and CS 2 h + HMP 2 h + SP600125 groups. Donor livers in the CS 4 h and CS 4 h + SP600125 groups were conventionally cold preserved for 4 h, whereas donor livers in the CS 2 h + HMP 2 h and CS 2 h + HMP 2 h + SP600125 groups were cold preserved for 2 h and then treated with HMP for 2 h. The preservation and perfusion solutions contained SP600125 (20 µM). Follow-up was conducted for 5 days after liver transplantation to compare the surgical outcomes by means of serological examination, pathological results, and survival rate. Results The most satisfactory outcome after liver transplantation was observed in the CS 2 h + HMP 2 h + SP600125 group, which presented with minimal damage of donor livers during 5 days’ follow-up. Additionally, serological examination, pathological results, and survival rate concurred in showing better results in the CS 2 h + HMP 2 h ± SP600125 group than in the CS 4 h ± SP600125 group. Conclusion HMP in combination with SP600125 has hepatoprotective properties and improves the quality and viability of porcine livers collected after DCD, thus improving prognosis after liver transplantation.

We report the clinical and laboratory findings and successful management of seven patients with critical coronavirus disease 2019 (COVID-19) requiring mechanical ventilation (MV). The patients were diagnosed based on epidemiological history, clinical manifestations, and nucleic acid testing. Upon diagnosis with COVID-19 of critical severity, the patients were admitted to the intensive care unit, where they received early noninvasive–invasive sequential ventilation, early prone positioning, and bundle pharmacotherapy regimen, which consists of antiviral, anti-inflammation, immune-enhancing, and complication-prophylaxis medicines. The patients presented fever (n = 7, 100%), dry cough (n = 3, 42.9%), weakness (n = 2, 28.6%), chest tightness (n = 1, 14.3%), and/or muscle pain (n = 1, 14.3%). All patients had normal or lower than normal white blood cell count/lymphocyte count, and chest computed tomography scans showed bilateral patchy shadows or ground glass opacity in the lungs. Nucleic acid testing confirmed COVID-19 in all seven patients. The median MV duration and intensive care unit stay were 9.9 days (interquartile range, 6.5–14.6 days; range, 5–17 days) and 12.9 days (interquartile range, 9.7–17.6 days; range, 7–19 days), respectively. All seven patients were extubated, weaned off MV, transferred to the common ward, and discharged as of the writing of this report. Thus, we concluded that good outcomes for patients with critical COVID-19 can be achieved with early noninvasive–invasive sequential ventilation and bundle pharmacotherapy.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become an immense public health burden, first in China and subsequently worldwide. Developing effective control measures for COVID-19, especially measures that can halt the worsening of severe cases to a critical status is of urgent importance. CASE SUMMARY: A 52-year-old woman presented with a high fever (38.8 °C), chills, dizziness, and weakness. Epidemiologically, she had not been to Wuhan where COVID-19 emerged and did not have a family history of a disease cluster. A blood test yielded a white blood cell count of 4.41 × 10(9)/L (60.6 ± 2.67% neutrophils and 30.4 ± 1.34% lymphocytes). Chest imaging revealed bilateral ground-glass lung changes. Based on a positive nasopharyngeal swab nucleic acid test result and clinical characteristics, the patient was diagnosed with COVID-19. Following treatment with early non-invasive ventilation and a bundle pharmacotherapy, she recovered with a good outcome. CONCLUSION: Early non-invasive ventilation with a bundle pharmacotherapy may be an effective treatment regimen for the broader population of patients with COVID-19.

Background Warm ischemia jeopardizes graft quality and recipient survival in donation after cardiac death (DCD) transplantation. Currently, there is no system to objectively evaluate the liver quality from DCD. The present study tried to use energy metabolites to evaluate the donor liver quality. Methods We divided 195 Sprague-Dawley rats into five groups: the control (n = 39), warm ischemic time (WIT) 15 min (n = 39), WIT 30 min (n = 39), WIT 45 min (n = 39), and WIT 60 min (n = 39) groups. Three rats from each group were randomly selected for pretransplant histologic evaluation of warm ischemia-related damage. The remaining 36 rats were randomly divided into donors and recipients of 18 liver transplantations, and were subjected to postoperative liver function and survival analyses. Between cardiac arrest and cold storage, liver energy metabolites including glucose, lactate, pyruvate, and glycerol were measured by microdialysis. The lactate to pyruvate ratio (LPR) was calculated. Results The changes in preoperative pathology with warm ischemia were inconspicuous, but the trends in postoperative pathology and aminotransferase levels were consistent with preoperative energy metabolite measurements. The 30-day survival rates of the control and WIT 15, 30, 45, and 60 min groups were 100%, 81.82%, 76.92%, 58.33%, and 25.00%, respectively. The areas under the receiver operating characteristic curves of glucose, lactate, glycerol, and LPR were 0.87, 0.88, 0.88, and 0.92, respectively. Conclusion Glucose, lactate, glycerol, and LPR are predictors of graft quality and survival outcomes in DCD transplantation.

Hemorrhoid refers to soft vein mass formed by varicosity of submucosal veins around the end of the rectum and subcutanceous veins of the anal canal. It is the most common anorectal disease. This article summarized the regular patterns, features and advantages of Professor Yu Hai-Bo’s acupuncture-moxibustion therapy for hemorrhoids, in order to guide the acupuncture treatment for hemorrhoids.

CXC chemokine ligand 16 (CXCL16) has been reported to exacerbate acute kidney injury induced by ischemia-reperfusion (IR). This study aimed to investigate the probable role of CXCL16 in hepatic IR injury during liver transplantation. The expression patterns of CXCL16 and its receptor CXC chemokine receptor 6 (CXCR6) were detected in mouse models of IR injury during liver transplantation and cell models of oxygen-glucose deprivation and reoxygenation (OGD/R)-induced hepatocyte injury using RT-qPCR, Western blot analysis and ELISA. CXCL16 expression was silenced in AML12 cells exposed to OGD/R conditions to determine the role of CXCL16 in cell apoptosis and injury. After treatment with CXCL16 and a p38 phosphorylation inhibitor, SB203580, we examined whether CXCL16 regulated p38 phosphorylation to impact hepatocyte injury. To verify the effects of CXCL16 and p38 phosphorylation in vivo, CXCL16 was silenced and p38 phosphorylation was activated in IR-treated mice. CXCL16 and CXCR6 were highly expressed in mouse models of IR injury and cell models of OGD/R-induced hepatocyte injury. Silencing of CXCL16 in AML12 cells resulted in diminished CXCR6 expression and alleviated OGD/R-exposed cell injury. CXCL16 treatment in AML12 cells brought about increased protein expressions of CXCR6 and p38 phosphorylation and elevated apoptosis rate of hepatocytes. Inhibition of p38 phosphorylation neutralized CXCL16-induced apoptosis of AML12 cells. Furthermore, CXCL16 knockdown in vivo relieved hepatic injury, which was reversed by activation of p38 phosphorylation. Taken together, silencing of CXCL16 might protect against IR injury during liver transplantation by reducing p38 phosphorylation, highlighting the potential of CXCL16 as a promising target for treatment against hepatic IR injury.

Background Lateral habenula nucleus (LHb) has recently been noted for its role in stress-induced depressive disorder. Yet little is known about the mechanisms by which external stimuli or depression induces pathological alteration in the LHb. Methods Chronic unpredictable mild stress (CUMS) was employed to model depressive-like behaviors in adult rats. We examined expressions of DNA methyltransferases (Dnmts) mRNA and protein and global DNA methylation levels in LHb of CUMS-induced depressive rats. Then 5-aza-2′-deoxycytidine (5-aza), a Dnmts inhibitor, was infused into the LHb of native rats to test the effects of hypomethylation in the LHb. The gene expressions in the LHb and the levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in dorsal raphe nucleus (DRN) were examined in 5-aza infusion rats by quantitative real-time PCR and high performance liquid chromatography, respectively. Results Rats were exposed to CUMS for 21 days and depressive-like behaviors were induced as expected. We observed significant decrease in mRNA and protein expressions of Dnmt1 and DNA hypomethylation in LHb of depressive rats. These phenomenon suggests that CUMS-induced depressive-like behaviors are related with DNA hypomethylation in the LHb. Local 5-aza infusion into LHb of native rat resulted in global DNA hypomethylation in the LHb and induced depressive-like behaviors which are featured with lack of interest and investment in the environment, behavioral despair and anhedonia. Moreover, DNA hypomethylation in the LHb increased transcription of β calcium/calmodulin dependent protein kinase II and glutamate receptor 1 in the LHb and attenuated the levels of 5-HT and 5-HIAA in the DRN. Our data suggested that alteration of DNA methylation in the LHb may control 5-HT neuronal activity in the DRN to regulate emotional state. Conclusions DNA hypomethylation in the LHb is involved in the development of depressive-like behavior and suitable methylation state contributes to the emotional stabilization.

Vascular smooth muscle (VSM) expresses calcium/calmodulin-dependent protein kinase II (CaMKII)-δ and -γ isoforms. CaMKIIδ promotes VSM proliferation and vascular remodeling. We tested CaMKIIγ function in vascular remodeling after injury. CaMKIIγ protein decreased 90% 14 d after balloon injury in rat carotid artery. Intraluminal transduction of adenovirus encoding CaMKIIγC rescued expression to 35% of uninjured controls, inhibited neointima formation (>70%), inhibited VSM proliferation (>60%), and increased expression of the cell-cycle inhibitor p21 (>2-fold). Comparable doses of CaMKIIδ2 adenovirus had no effect. Similar dynamics in CaMKIIγ mRNA and protein expression were observed in ligated mouse carotid arteries, correlating closely with expression of VSM differentiation markers. Targeted deletion of CaMKIIγ in smooth muscle resulted in a 20-fold increase in neointimal area, with a 3-fold increase in the cell proliferation index, no change in apoptosis, and a 60% decrease in p21 expression. In cultured VSM, CaMKIIγ overexpression induced p53 mRNA (1.7 fold) and protein (1.8-fold) expression; induced the p53 target gene p21 (3-fold); decreased VSM cell proliferation (>50%); and had no effect on expression of apoptosis markers. We conclude that regulated CaMKII isoform composition is an important determinant of the injury-induced vasculoproliferative response and that CaMKIIγ and -δ isoforms have nonequivalent, opposing functions.—Saddouk, F. Z., Sun, L.-Y., Liu, Y. F., Jiang, M., Singer, D. V., Backs, J., Van Riper, D., Ginnan, R., Schwarz, J. J., Singer, H. A. Ca2+/calmodulin-dependent protein kinase II-γ (CaMKIIγ) negatively regulates vascular smooth muscle cell proliferation and vascular remodeling.

“Transplantation” (Volume 97, Number 8, April 27, 2014) published an open letter from Professor Delmonico along with other seven professors to Mr. Xi Jinping, President of the People's Republic of China: China's Fight Against Corruption in Organ Transplantation. The article sharply posed this concern, thus evoking great attention at home and abroad within the transplant community. To this end, we hereby state our views and declare our position with regard to the concerns mentioned in the open letter about China's organ transplant undertaking.

A series of novel podophyllotoxin derivatives was synthesized by coupling 4β-amino-4′-demethyl-4-desoxypodophyllotoxin (3a) or 4β-amino-4-desoxypodophyllotoxin (3b) with N-substituted 5-formylindole (2a–h). Their structures were identied by spectroscopic techniques. These novel derivatives were evaluated for cytotoxicity in vitro against HepG2 and HeLa cell lines. Compared with etoposide, most of the compounds showed more potent cytotoxicities against two tumor cell lines. Judging from the IC50 values, compound 5n is a promising agent, which is about 15 and 5 times more toxic than etoposide against HepG2 and HeLa cell lines, respectively.

China has developed a new national program for deceased-organ donation to address the need for organ transplantation in the country. The program adheres to the World Health Organization (WHO) guiding principles, is compliant with the Declaration of Istanbul, and respects the cultural and social values of the Chinese people. The experience of pilot trials conducted between 2010 and 2012 was evaluated to generate a comprehensive design of a national program of organ donation and transplantation for implementation throughout China. The legal framework for this program was established from a series of legislative steps since 2007. Accountable national committees have been established to oversee activities of organ donation and transplantation across the nation. The Ministry of Health (MOH) has accredited 164 organ transplant hospitals in China, each of which has an organ procurement organization (OPO) to conduct organ donation and organ recovery. National protocols for deceased-organ donation in China include category I (organ donation after brain death), category II (organ donation after circulatory death), and category III (organ donation after brain death followed by circulatory death). The China Organ Transplant Response System (COTRS) has been developed to allocate organs equitably and transparently. Scientific registries have been established to evaluate the performance of transplant centers and OPOs. China is in the process of implementing a new national program for deceased-organ donation. The program includes a unique approach of organ donation, China category III, which will be promulgated throughout China and is intended to gain widespread acceptance of Chinese society.

The multifunctional Ca2+/calmodulin-dependent protein kinase II δ-isoform (CaMKIIδ) promotes vascular smooth muscle (VSM) proliferation, migration, and injury-induced vascular wall neointima formation. The objective of this study was to test if microRNA-30 (miR-30) family members are endogenous regulators of CaMKIIδ expression following vascular injury and whether ectopic expression of miR-30 can inhibit CaMKIIδ-dependent VSM cell function and neointimal VSM hyperplasia induced by vascular injury. The CaMKIIδ 3′UTR contains a consensus miR-30 binding sequence that is highly conserved across species. A significant decrease in miR-30 family members and increase in CaMKIIδ2 protein expression, with no change in CaMKIIδ mRNA expression, was observed in medial layers of VSM 7 days post-injury. In vitro, overexpression of miR-30c or miR-30e inhibited CaMKIIδ2 protein expression by ~50% in cultured rat aortic VSM cells, and inhibited VSM cell proliferation and migration. In vivo, lenti-viral delivery of miR-30c into injured rat carotid arteries prevented the injury-induced increase in CaMKIIδ2. Furthermore, neointima formation was dramatically inhibited by lenti-viral delivery of miR-30c in the injured medial smooth muscle. These studies define a novel mechanism for regulating CaMKIIδ expression in VSM and provide a new potential therapeutic strategy to reduce progression of vascular proliferative diseases, including atherosclerosis and restenosis.

Objectives This study aims to test the effects of TAK-242 on liver transplant viability in a model of swine Maastricht-category-III cardiac death. Methods A swine DCD Maastricht-III model of cardiac death was established, and TAK-242 was administered prior to the induction of cardiac death. The protein and mRNA level of TLR4 signaling pathway molecules and cytokines that are important in mediating immune and inflammatory responses were assessed at different time points following the induction of cardiac death. Results After induction of cardiac death, both the mRNA and protein levels of key molecules (TLR4, TRAF6, NF-ϰB, ICAM-1, MCP-1 and MPO), TNF-α and IL-6 increased significantly. Infusion of TAK-242 1 h before induction of cardiac death blocked the increase of immune and inflammatory response molecules. However, the increase of TLR4 level was not affected by infusion of TAK-242. Histology study showed that infusion of TAK-242 protect liver tissue from damage during cardiac death. Conclusions These results indicates that TLR4 signaling pathway may contribute to ischemia/reperfusion injury in the liver grafts, and blocking TLR4 pathway with TAk-242 may reduce TLR4-mediated tissue damage.

To calculate soot for a high-pressure common rail diesel engine a new soot model (TP model) is presented.. In soot source term phase, when zone temperature T

Author Affiliations: Department of Liver Surgery, Peking Union Medical College Hospital; National Organ Transplant Committee, Ministry of Health, Beijing 100000, China (Huang JF); The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, China (Zheng SS); The First Hospital of China Medical University, Shenyang 110001, China (Liu YF); Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong; China Organ Transplant Response System Research Center, Shenzhen 518000, China (Wang HB); Centre for Renal and Transplant Research, Westmead Millenium Institute, Sydney University, Sydney, Australia (Chapman J and O'Connell P); Section of Transplantation, Liver Transplantation and Hepatobiliary Surgery, University of Chicago, Chicago, IL, USA (Millis M); Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA (Fung J) and Department of Surgery, Massachusetts General Hospital, Boston, MA, USA (Delmonico F)

Objective To study the serum protein fingerprint of patients with pancreatic cancer and to screen for protein molecules closely related to pancreatic cancer during the onset and progression of the disease using surface-enhanced laser desorption and ionization time of fight mass spectrometry (SELDI-TOF-MS).

OBJECTIVE To establish a serum protein pattern model for screening pancreatic cancer. METHODS Twenty-nine serum samples from patients with pancreatic cancer were collected before surgery, and an additional 57 serum samples from age and sex-matched individuals without cancer were used as controls. WCX magnetic beans and a PBS II-C protein chip reader (Ciphergen Biosystems Inc) were employed to detect the protein fingerprint expression of all serum samples. The resulting pro fi les comparing serum from cancer and normal patients were analyzed with the Biomarker Wizard system, to establish a model using the Biomarker Pattern system software. A double-blind test was used to determine the sensitivity and specificity of the model. RESULTS A group of 4 biomarkers (relative molecular weights were 5,705 Da, 4,935 Da, 5,318 Da, 3,243 Da) were selected to set up a decision tree to produce the classification model to effectively screen pancreatic cancer patients. The results yielded a sensitivity of 100% (20/20), specificity of 97.4% (37/38). The ROC curve was 99.7%. A double-blind test used to challenge the model resulted in a sensitivity of 88.9% and a specificity of 89.5%. CONCLUSION New serum biomarkers of pancreatic cancer have been identified. The pattern of combined markers provides a powerful and reliable diagnostic method for pancreatic cancer with high sensitivity and specificity.

Granular cell tumor is rare and accounts for approximately 0.5 % of all soft tissue tumors. The malignant granular cell tumor, especially cutaneous malignant granular cell tumor is extremely rare. The present case is the first patient of primary cutaneous malignant granular cell tumor reported from China in English. A review of the literature is performed, and the presentation, position, pathological diagnosis, treatment and prognosis of the patients with cutaneous malignant granular cell tumor of the reported cases before is analysed.

Aims We have compared hypothermic oxygenated machine perfusion (HOPE) with simple cold storage (SCS) in liver preservation with a porcine model of donor after cardiac death (DCD). Methods A DCD model was developed in 10 hybrid pigs by apnea. Livers were harvested after 30 min of warm ischemia (WI) and randomly preserved using HOPE (HOPE group, five pigs, dual perfusion via portal vein and hepatic artery) or SCS (SCS group, five pigs) methods. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose, lactic acid, and pyruvic acid were measured by microdialysis analyzer. Results Histological morphology of liver tissue was significantly affected by 30 min of WI. HOPE significantly delayed histological morphology change and cell apoptosis. Release of ALT and AST was significantly higher in SCS group compared to HOPE group (p

Introduction Recent studies examining the association of Toll-like receptor 3 (TLR3) gene polymorphisms with the risk of developing various types of cancer have reported conflicting results. Clarifying this association could advance our knowledge of the influence of TLR3 single nucleotide polymorphisms (SNPs) on cancer risk. Methods We systematically reviewed studies that focused on a collection of 12 SNPs located in the TLR3 gene and the details by which these SNPs influenced cancer risk. Additionally, 14 case-control studies comprising a total of 7997 cases of cancer and 8699 controls were included in a meta-analysis of 4 highly studied SNPs (rs3775290, rs3775291, rs3775292, and rs5743312). Results The variant TLR3 genotype rs5743312 (C9948T, intron 3, C > T) was significantly associated with an increased cancer risk as compared with the wild-type allele (odds ratio [OR] = 1.11, 95 % confidence interval [CI] = 1.00–1.24, P = 0.047). No such association was observed with other TLR3 SNPs. In the stratified analysis, the rs3775290 (C13766T, C > T) variant genotype was found to be significantly associated with an increased cancer risk in Asian populations. Additionally, the rs3775291 (G13909A, G > A) variant genotype was significantly associated with an increased cancer risk in Asians, subgroup with hospital-based controls, and subgroup with a small sample size. Conclusion After data integration, our findings suggest that the TLR3 rs5743312 polymorphism may contribute to an increased cancer risk.

Airway smooth muscle (ASM) is a key target cell in allergen-induced asthma known to contribute to airway hyperresponsiveness (AHR) and chronic airway remodeling. Changes in ASM calcium homeostasis have been shown to contribute to AHR although the mechanisms and Ca(2+) signal effectors are incompletely understood. In the present study, we tested the function of ASM multifunctional protein kinase Ca(2+)/calmodulin-dependent kinase II (CaMKII) isoforms CaMKIIδ and CaMKIIγ in allergen-induced AHR and airway remodeling in vivo. Using a murine model of atopic asthma, we demonstrate that CaMKIIδ protein is upregulated in ASM derived from ovalbumin (OVA)-treated animals compared to controls. A genetic approach to conditionally knock out smooth muscle CaMKIIδ and CaMKIIγ in separate Cre-loxp systems was validated, and using this loss-of-function approach, the function of these CaMKII isoforms was tested in ovalbumin (OVA)-induced airway remodeling and AHR. OVA treatment in control mice had no effect on ASM remodeling in this model of AHR, and CaMKIIδ knockouts had no independent effects on ASM content. However, at 1 day post-final OVA challenge, OVA-induced AHR was eliminated in the CaMKIIδ knockouts. OVA-induced peribronchial inflammation and bronchoalveolar lavage fluid (BALF) levels of the Th2 cytokine IL-13 were significantly decreased in the CaMKIIδ knockouts. Unexpectedly, we found increased peribronchial eosinophils in the smooth muscle CaMKIIδ knockouts compared to control animals at 1 day post-final challenge, suggesting that lack of ASM CaMKIIδ delays the progression of AHR rather than inhibiting it. Indeed, when AHR was determined at 7 days post-final OVA challenge, CaMKIIδ knockouts showed robust AHR while AHR was fully resolved in OVA-challenged control mice. These in vivo studies demonstrate a role for smooth muscle CaMKIIδ in promoting airway inflammation and AHR and suggest a complex signaling role for CaMKIIδ in regulating ASM function. These studies confirm the diverse roles of ASM cells as immune effectors that control AHR and call for further studies into CaMKIIδ-mediated signaling in ASM cells during disease.

Huaier aqueous extract, the main active constituent of Huaier proteoglycan, has antihepatocarcinoma activity in experimental and clinical settings. However, the potential and associated antihepatoma mechanisms of Huaier extract are not yet fully understood. Therefore, in this study, we aimed to elucidate the inhibitory proliferation effect of Huaier extract on apoptosis and cycle of HepG2 and Bel-7402 cells. Our data demonstrated that incubation with Huaier extract resulted in a marked decrease in cell viability dose-dependently. Flow cytometric analysis showed that a 48 h treatment of Huaier extract caused cell apoptosis. Typical apoptotic nucleus alterations were observed with fluorescence microscope after Hoechst staining. Immunoblot analysis further demonstrated that Huaier extract activated caspase 3 and PARP. Additionally, Huaier extract inhibited the activity of p-ERK, p-p38, and p-JNK in terms of MAPK. Furthermore, Huaier extract induced HCC cells arrest in S phase and decreased the cycle related protein expression ofβ-catenin and cyclin D1. Studies with JNK specific inhibitor, SP600125, showed that Huaier extract induced S phase arrest and decreasedβ-catenin and cyclin D1 expression via JNK signaling pathway. In conclusion, we verify that Huaier extract causes cell apoptosis and induces hepatocellular carcinoma cells arrest in S phase via JNK pathway, which advances our understanding on the molecular mechanisms of Huaier extract in hepatocarcinoma management.

MicroRNAs could mediate the targeted coding gene and the targeted non-coding RNA to form endogenous competition, which have an important regulatory role in tumorigenesis of many types of cancer, including hepatocellular carcinoma. The goal of this study was to characterize the role of miR-200b in the pathogenesis of hepatocellular carcinoma. We identified miR-200b that was predicted to regulate RhoA and circ_000839. Our data establish that miR-200b is expressed at a relatively low level in hepatocellular carcinoma ( p

The promoter region of the microRNA pri-miR-34b/c has a potentially functional polymorphism, rs4938723, located in a typical CpG island. Studies of the association between pri-miR-34b/c rs4938723 polymorphism and risks of various cancers have had inconsistent results. We therefore conducted a meta-analysis of nine studies that included 6,036 cancer patients and 7,490 controls to address this association. Overall, this meta-analysis showed the pri-miR-34b/c rs4938723 TC heterozygote to be significantly associated with increased risk of overall cancers compared with the wild-type TT genotype (P = 0.010, odds ratio (OR) = 1.10, 95 % confidence interval (CI) 1.02–1.18). In stratified analysis, the TC heterozygote was significantly associated with increased cancers risks in digestive tract cancers, in hepatocellular cancer, in Asian population and in the large-sample subgroup. The CC genotypes of rs4938723 were also associated with increased hepatocellular cancer risk but associated with decreased colorectal cancer risk in the stratification analysis by a single cancer type. Thus our meta-analysis suggests that the pri-miR-34b/c rs4938723 TC heterozygote contributes to increased overall cancer risks, as well as shown in digestive tract cancers, in hepatocellular cancer, in Asian population and in the large-sample subgroup. This rs4938723 SNP showed an opposite tendency orientation between the hepatocellular cancer and colorectal cancer risks. Large-sample studies are needed to verify our findings.

This study aims to evaluate the ischemic injury of the liver in a porcine model of cardiac death assessed by in vivo microdialysis. A porcine model of cardiac death was established by the suffocation method. Metabolic indicators were monitored using the microdialysis technique during warm ischemia time (WIT) and cold ischemia time (CIT). Pathological changes in ischemic-injured livers were observed by haematoxylin–eosin staining. The predictive values of biochemical parameters regarding the liver donor were evaluated by receiver operating characteristic curve analysis. All statistical analyses were conducted using the SPSS 18.0 software (SPSS Inc, Chicago, Illinois, USA). The degree of warm ischemic injury of the livers increased with prolonged WIT. Serum glucose, glycerol, pyruvate, lactic acid levels and lactate-to-pyruvate (L/P) ratio increased gradually during WIT. Results from Pearson correlation analyses indicated that serum lactate level and L/P ratio were positively associated with the degree of warm ischemic injury of the livers. The degree of cold ischemic injury of the livers gradually increased after 12 h CIT. Serum glucose, lactic acid and L/P ratio achieved a peak after 6–8 h of CIT, but gradually decreased with prolonged CIT. The peak of glycerol occurred after 8 h of CIT, while no changes were found with prolonged CIT. Serum pyruvate level exhibited an increasing trend after 12 h CIT. Our results confirmed that serum glucose and lactate levels were negatively correlated with cold ischemic injury of the liver. However, serum glycerol and pyruvate levels showed positive correlations with cold ischemic injury of the liver. The liver donor was unavailable after 30 min WIT and 24 h CIT. The cut-off value of serum lactate level for warm ischemic injury of the livers was 2.374 with a sensitivity (Sen) of 90 % and specificity (Spe) of 95 %; while the L/P radio was 0.026 (Sen = 80 %, Spe = 83 %). In addition, the cut-off values of serum glucose, lactate, glycerol and pyruvate levels for cold ischemic injury of the livers were 0.339 (Sen = 100 %, Spe = 77 %), 1.172 (Sen = 100 %, Spe = 61 %), 56.359 (Sen = 100 %, Spe = 65 %) and 0.020 (Sen = 100 %, Spe = 67 %), respectively. Our findings provide empirical evidences that serum glucose, lactate levels and L/P ratio may be good indicators for the degree of warm ischemic injury of the livers after cardiac death; while serum glucose, lactate, glycerol and pyruvate levels may be important in predicting cold ischemic injury.

Background Expanded criteria donors (ECDs) are currently accepted as potential sources to increase the donor pool and to provide more chances of kidney transplantation for elderly recipients who would not survive long waiting periods. Hypothermic machine perfusion (HMP) is designed to mitigate the deleterious effects of simple cold storage (CS) on the quality of preserved organs, particularly when the donor is in a marginal status. Methods We compared the transplant outcomes in patients receiving ECD kidneys with either HMP or CS graft preservation. Articles from the MEDLINE, EMBASE and Cochrane Library databases were searched and all studies reporting outcomes from HMP versus CS methods of kidney preservation were included in this meta-analysis. The parameters analyzed included the incidence of delayed graft function (DGF), primary non-function (PNF) and one-year graft and patient survival. Results A total of seven studies qualified for the review, involving 2374 and 8716 kidney grafts with HMP or CS preservation respectively, all from ECD donors. The incidence of delayed graft function (DGF) was significantly reduced with an odd ratio(OR) of 0.59 (95% CI 0.54–0.66, P

The epithelial sodium channel (ENaC) plays an important role in controlling Na+ homeostasis, extracellular fluid volume, and blood pressure. Copper metabolism Murr1 domain-containing protein 1 (COMMD1) interacts with ENaC and downregulates ENaC. COMMD1 belongs to the COMMD family consisting of COMMD1–10, and all COMMD family members share a C-terminal COMM domain. Here, we report that COMMD2–10 also interacts with ENaC, and COMMD3 and COMMD9 were selected for further study. Amiloride-sensitive current in mammalian epithelia expressing ENaC was significantly reduced by COMMD3 or COMMD9, and ENaC expression at the cell surface was significantly decreased in the presence of COMMD3 or COMMD9. COMMD3 and COMMD9 retained their ability to reduce current when COMMD1 was knocked down. COMMD3 and COMMD9 were widely expressed in kidney and were colocalized with ENaC in renal collecting duct cells. These data suggest that COMMD3 and COMMD9 may be endogenous regulators of ENaC to regulate Na+ transport through altering ENaC cell surface expression.

Ischemic stroke is a major composition of cerebrovascular disease, seriously threatening to human health in the world. Activin A (ActA), belonging to transforming growth factor-beta (TGF-β) super family, plays an important role in the hypoxic-ischemic brain injury through ActA/Smads pathway. While as an essential phosphorylation assistor in TGF-β signaling, the functions and mechanisms of smad anchor for receptor activation (SARA) in ischemic brain injury remain poorly understood. To solve this problem and explore the pathological processes of ischemic stroke, we used an Oxygen-Glucose deprivation (OGD) model in nerve growth factor-induced differentiated rattus PC12 pheochromocytoma cells and down regulated the expressions of SARA by RNA interference technology. Our results showed that the repression of SARA before OGD exposure reduced the expressions of Smad2, 3, 4 mRNA and the phosphorylation rate of Smad2 protein, but it did not affect the mRNA expressions of Smad7. After OGD treatment, ActA/Smads pathway was activated and the expression of SARA in the SARA pre-repression group was significantly up-regulated. The pre-repression of SARA increased the sensitivities of nerve-like cells to OGD damage. Moreover, the mRNA expression of Smad7 which was supposed to participate in the negative feedback of ActA/Smads pathway was also elevated due to OGD injury. Taken together, these results suggest a positive role of SARA in assisting the phosphorylation of Smad2 and maintaining the neuron protective effect of ActA/Smads pathway.

Cerebral ischemia is one of the most common diseases treated by acupuncture therapeutics. Recent studies indicated that acupuncture treatment by needling the conception and governor vessels had positive effects in promoting neural regeneration in patients after cerebral ischemia injury. Acupuncture intervention could continuously promote the proliferation and differentiation of the neural stem cells in the brain, obviously up-regulate expression of growth factors, accelerate angiogenesis and inhibit apoptosis. Hence, it is necessary to present an exhaustive review on the mechanisms. The present review gives a detailed description of pathological changes of cerebral ischemia and acupuncture intervention applied to the conception and governor vessels, and proposes research prospects in the future.

BACKGROUND/AIMS There are studies that report that liver metastases rarely occur in patients with cirrhosis. This study evaluates the relationship between the incidence of liver metastases from colorectal cancer (CRC) and chronic hepatitis virus infection in patients. METHODOLOGY Three hundred and fifty-four cases of advanced CRC from our hospital were evaluated. The patients were divided into a chronic hepatitis virus infection group and a non-hepatitis virus infection group. The two groups were compared regarding the incidence of colorectal liver metastases and survival. The criterion of colorectal liver metastases was based on liver CT examination and intraoperative exploration results. RESULTS There were two cases with colorectal liver metastases among the seventy cases of the chronic hepatitis virus infection group. The rate of liver metastases was 2.86%. There were 48 cases with colorectal liver metastases among 284 cases of the non-hepatitis virus infection. The rate of liver metastases was 16.9%. The incidence of colorectal liver metastases between the two groups was significantly different (p

A representative synthetic process of derivatizing the natural product podophyllotoxin utilizing the copper-catalyzed azide–alkyne cycloaddition (CuAAC) is described including molecular design, reaction optimization and X-ray structure confirmation. Evaluation of cytotoxicity against human cancer cell lines (Hela, K562 and K562/A02) using MTT assay proves that these triazole derivatives have good antitumor activities. High activities toward the drug resistant K562/A02 cell line reveal promising future for these derivatives. The rarely prepared 1,5-disubstituted triazole isomers, which would be omitted by the “click chemistry”, were found to have superior cytotoxicities to that of the 1,4-disubstituted isomers.

Background. Three commonly used sutures were tested in a pig model of bile duct anastomosis to assess their relative contributions to inflammation and scarring.Methods. Thirty pigs were randomised to bile duct division and anastomosis with either polyglyconate (Maxon), polyglactin 910 (Vicryl) or polypropylene (Prolene). Half the animals were sacrificed at two weeks and the remainder at 23 weeks. Anastomoses were assessed by cholangiography, scanning electron microscopy and light microscopy.Results. There was less short term histological reaction with the two monofilament materials, Prolene and Maxon, compared to the braided suture Vicryl. Maxon was associated with less long term inflammation than Prolene, was found to handle better, and has an advantage over Prolene by being absorbable.Conclusion. Maxon is an optimal suture for bile duct anastomoses. Its long term absorption characteristics make it suitable for situations where bile duct healing may be delayed.

General anesthetics are believed to induce amnesia. However, propofol can ameliorate cognitive deficits induced by electroconvulsive therapy (ECT), a treatment for mental disorders. This study aimed at investigating the possible molecular mechanism as well as the effects of propofol on learning-memory impairment in depressed rats induced by ECS (electroconvulsive shock, the analog of ECT to animals). Rats were treated with ECS (or sham ECS) pretreated with intraperitoneal injection of propofol (100 mg/kg) (or normal saline, 0.01 l/kg) after being treated with chronic unpredictable mild stresses to reproduce an animal model of depression. Sucrose preference test, open field test, and Morris water maze were used to assess behavioral changes. Hippocampal glutamate (Glu) and γ-aminobutyric acid (GABA) levels were measured with liquid chromatography, and glutamic acid decarboxylase 65 (GAD65) was assayed immunohistochemically. Additionally, rats undergoing ECS that were pretreated with pentobarbital sodium (45 mg/kg) were included for behavioral tests and electroencephalogram recording for comparison with rats undergoing ECS that were pretreated with propofol or normal saline. ECS rats pretreated with propofol or pentobarbital sodium exhibited similar decreased seizure durations as compared with ECS rats pretreated with normal saline. ECS pretreated with normal saline aggravated learning-memory deficits whereas ECS pretreated with propofol or pentobarbital sodium did not. Rats undergoing ECS pretreated with propofol showed better memory than those undergoing ECS after pretreatment with pentobarbital sodium. ECS pretreated with normal saline downregulated the ratio of Glu/GABA and upregulated GAD65 expression; all these molecular changes were nearly normalized to the level of control group by ECS pretreated with propofol. There were no significant differences of depressive behaviors between groups treated with ECS. The data suggest that propofol alleviated ECS-induced learning-memory impairment without interfering with the antidepressant efficacy of ECS, possibly by inhibiting excessive expression of GAD65 and maintaining the balance between glutamatergic and GABAergic amino acids neurotransmitters in the hippocampus.

The epithelial sodium channel (ENaC) is important for the long-term control of Na+ homeostasis and blood pressure. Our previous studies demonstrated that Copper Metabolism Murr1 Domain-containing protein 1 (COMMD1; previously known as Murr1), a protein involved in copper metabolism, inhibited amiloride-sensitive current in Xenopus laevis oocytes expressing ENaC ( J Biol Chem 279: 5429, 2004). In this study, we report that COMMD1 inhibits amiloride-sensitive current in mammalian epithelial cells expressing ENaC, that the COMM domain of COMMD1 is sufficient for this effect, and that knockdown of COMMD1 increases amiloride-sensitive current. COMMD1 is coexpressed with ENaC in rat kidney medulla cells. COMMD1 increased ubiquitin modification of ENaC and decreased its cell surface expression. COMMD1 abolished insulin-stimulated amiloride-sensitive current and attenuated the stimulation of current by activated serum and glucocorticoid-regulated kinase (SGK1). COMMD1 was found to interact with both SGK1 and Akt1/protein kinase B, and knockdown of COMMD1 enhanced the stimulatory effect of both SGK1 and Akt1 on amiloride-sensitive current. COMMD1's effects were reduced in the presence of ENaC proteins containing PY motif mutations, abolished in the presence of a dominant negative form of Nedd4–2, and knockdown of COMMD1 reduced the inhibitory effect of Nedd4–2 on ENaC, but did not enhance current when Nedd4–2 was knocked down. These data suggest that COMMD1 modulates Na+ transport in epithelial cells through regulation of ENaC cell surface expression and this effect is likely mediated via Nedd4–2.

ObjectiveTo observe clinical therapeutic effects of acupuncture combined with music therapy for treatment of cerebral palsy.MethodsSixty children with cerebral palsy were randomly divided into an acupuncture group (Group Acup.) and an acupuncture plus music group (Group Acup.+ M). Simple acupuncture was applied in Group Acup., and acupuncture at 5 groups of points plus music were applied in Group Acup. +M. The treatment was given once every two days with 3 treatments weekly, and 36 treatments constituted a therapeutic course. Therapeutic effects including movement improvement were observed for comparison after 3 courses of treatments.ResultsThe comprehensive functions were elevated in both groups, and the total effective rate in Group Acup. + M was obviously better than that in Group Acup (P

Background. Insulin keeps the liver in a metabolically vigorous state. However, organ preservation aims to decrease the metabolic rate. The objective of this study was to clarify the effect of insulin used in University of Wisconsin (UW) preservation solution on the liver graft. Methods. The liver grafts were preserved by UW solution with or without insulin for 7, 9, and 24 hr, respectively. The influence of insulin was studied by 7-day survival rate, liver function, morphology, and intragraft gene expression 24 hr after transplantation. Morphology was studied on the preserved grafts. Results. The morphology of the graft in the insulin group showed more severe ischemia-reperfusion injury. The 7-day graft survival rates of the 7-hr subgroups with and without insulin were 55% and 93%, respectively (P=0.02). In the 9-hr subgroups, the survival rates were 0% and 78%, respectively (P=0.002). The serum levels of aspartate aminotransferase (AST) (P=0.008) and alanine aminotransferase (ALT) (P=0.032) were higher in the 7-hr subgroup with insulin. The same trend was found in the 9-hr subgroups (AST, P=0.016; ALT, P=0.016). The expression level of 215 genes were much lower at 24 hr after transplantation in the grafts preserved with insulin than in those preserved without insulin, and most of the genes were related to metabolic activities. Conclusions. Insulin in UW solution may exacerbate graft ischemic injury and decrease the graft survival rate in rat liver transplantation. Insulin, in the absence of glucose in UW solution, may exhaust the metabolic activity of the liver graft. It is harmful rather than helpful for isolated rat liver grafts preserved in UW solution.

From 1962 to 1994, 1200 patients with periampullary carcinoma had laparotomy in our department. Of these cases, 320 underwent pancreatoduodenectomy (PD); the resection rate was 25.8%. Hospital mortality was 23 cases (7.19%), and hospital morbidity was 69 cases (21.9%). The 320 PD, 214 were men and 106 women, ranging in age from 26 to 73 years, with a median of 52.9 years. The lesions of the 320 cases were carcinoma in the head of pancreas (81 cases), in the common bile duct (85), in the ampulla of Vater (104), and in the duodenum (50). The method of resection we preferred is to follow the order of gallbladder, bile duct, stomach, proximal jejunum, and duodenum initially and leave the pancreas until last; this method provides excellent exposure of the uncinate process and controls bleeding easily. Gastrojejunual anastomosis was the retrocolic procedure. The end of the jejunum is brought into the upper abdomen in a retrocolic position, but anterior to the mesenteric vessels. Pancreatic fistula is a common and serious complication following PD. From 1962 to 1970, 43PDs with end-to-side anastomosis without pancreatic drainage were performed; the fistula occurred in 10 patients and 6 died; thus, we changed the method to end-to-end anastomosis between the pancreas and jejunum, and in 14 patients with internal drainage by use of a short tube, fistula occurred in 2 cases. We then changed to a long catheter for external drainage for 237 cases, and the fistula occurred only in 3 cases. Our data show that the postoperative survival rate is poor for pancreatic carcinoma. The 1-year survival rate is no more than 50%, and the 3-year rate is only 13.58%. However, for carcinoma of the ampulla of Vater and common bile duct, the result is better; the 5-year survival rate for carcinoma of the ampulla of Vater is 41.54%, which is the best result.

Background Although laparoscopic surgery has been available for a long time and laparoscopic cholecystectomy has been performed universally, it is still not clear whether open appendectomy (OA) or laparoscopic appendectomy (LA) is the most appropriate surgical approach to acute appendicitis. The purpose of this work is to compare the therapeutic effects and safety of laparoscopic and conventional "open" appendectomy by means of a meta-analysis. Methods A meta-analysis was performed of all randomized controlled trials published in English that compared LA and OA in adults and children between 1990 and 2009. Calculations were made of the effect sizes of: operating time, postoperative length of hospital stay, postoperative pain, return to normal activity, resumption of diet, complications rates, and conversion to open surgery. The effect sizes were then pooled by a fixed or random-effects model. Results Forty-four randomized controlled trials with 5292 patients were included in the meta-analysis. Operating time was 12.35 min longer for LA (95% CI: 7.99 to 16.72, p < 0.00001). Hospital stay after LA was 0.60 days shorter (95% CI: -0.85 to -0.36, p < 0.00001). Patients returned to their normal activity 4.52 days earlier after LA (95% CI: -5.95 to -3.10, p < 0.00001), and resumed their diet 0.34 days earlier(95% CI: -0.46 to -0.21, p < 0.00001). Pain after LA on the first postoperative day was significantly less (p = 0.008). The overall conversion rate from LA to OA was 9.51%. With regard to the rate of complications, wound infection after LA was definitely reduced (OR = 0.45, 95% CI: 0.34 to 0.59, p < 0.00001), while postoperative ileus was not significantly reduced(OR = 0.91, 95% CI: 0.57 to 1.47, p = 0.71). However, intra-abdominal abscess (IAA), intraoperative bleeding and urinary tract infection (UIT) after LA, occurred slightly more frequently(OR = 1.56, 95% CI: 1.01 to 2.43, p = 0.05; OR = 1.56, 95% CI: 0.54 to 4.48, p = 0.41; OR = 1.76, 95% CI: 0.58 to 5.29, p = 0.32). Conclusion LA provides considerable benefits over OA, including a shorter length of hospital stay, less postoperative pain, earlier postoperative recovery, and a lower complication rate. Furthermore, over the study period it was obvious that there had been a trend toward fewer differences in operating time for the two procedures. Although LA was associated with a slight increase in the incidence of IAA, intraoperative bleeding and UIT, it is a safe procedure. It may be that the widespread use of LA is due to its better therapeutic effect.

The actions of erythromycin lactobionate and porcine motilin on trans-sphincteric flow and simultaneous sphincter of Oddi motility were studied in 15 anaesthetized Australian Brush-tailed possums (Trichosurus vulpecula). Erythromycin (25-200 micrograms/kg) and motilin (25-200 ng/kg) were administered as graded doses by close intraarterial injection. Trans-sphincteric flow was measured as inflow and outflow. Both motilin and erythromycin decreased trans-sphincteric inflow (both P0.0001) and outflow (P0.0001 and P = 0.0017 respectively) in a dose-dependent manner. The highest dose of each agent abolished trans-sphincteric flow. These agents increased sphincter of Oddi phasic contraction frequency and basal pressure up to 2 and 3 fold respectively (P0.05). The amplitude of the sphincter of Oddi phasic contractions were not influenced in any consistent fashion by either agent. The durations of the responses (trans-sphincteric inflow) elicited by erythromycin and motilin were dose dependent (P = 0.0225 and P = 0.0001 respectively). The actions of erythromycin (200 micrograms/kg) or motilin (100 ng/kg) on trans-sphincteric flow and sphincter of Oddi motility were not influenced by neural blockade with tetrodotoxin. These findings support the hypothesis that erythromycin acts as a motilin agonist and both substances increase the resistance to flow through the sphincter of Oddi by raising the basal pressure and frequency of contractions.