1-磷酸鞘胺醇受体3参与巨噬细胞迁移及脓毒症诱导的心肌损伤

目的探讨巨噬细胞中1-磷酸鞘胺醇受体(sphingosine 1-phosphate receptor,S1PR)的表达及其作用,观察干预S1PR3(S1P3)对脂多糖诱导的心肌损伤的影响。方法传代培养小鼠Ana-1巨噬细胞,给予脂多糖(lipopolysaccharide,LPS,100 ng/ml)刺激或S1P3特异性抑制剂CAY-10444(10μmol/L)干预,细胞随机分为对照组、LPS组、CAY-10444组、CAY-10444预处理2h+LPS组,Transwell小室观测巨噬细胞迁移,蛋白免疫印迹检测巨噬细胞S1PR的表达,并检测p-Akt/Akt蛋白水平。在体实验,6~8周龄雄性C57/B6小鼠,随机分为对照组、LPS组、CAY-10444组、CAY-10444干预+LPS组,每组12只,LPS(10 mg/kg)腹腔注射,或CAY-10444 1 mg/kg于LPS诱导后30 min腹腔注射干预,24 h后取心脏组织HE染色观察病理改变,免疫组化染色观察巨噬细胞浸润程度以及炎症因子的表达情况,实时荧光定量PCR检测心肌损伤标记分子BNP、巨噬细胞表面分子F4/80、炎症因子TNF-α、IL-1β、IL-6的mRNA水平。结果与对照组比较,LPS诱导巨噬细胞大量迁移S1P3蛋白表达增加(P0.01),p-Akt Ser473/Akt表达上调(P0.01);与LPS组相比,S1P3抑制剂CAY-10444干预后再给予LPS刺激,巨噬细胞迁移被抑制(P0.01),p-Akt Ser473/Akt表达也降低(P0.01);在体实验,LPS诱导小鼠后BNP mRNA水平明显上调(P0.01),同时F4/80以及炎症因子TNF-α、IL-1β、IL-6的mRNA水平上调(P0.01),HE染色可见心肌损伤及炎细胞浸润,免疫组化染色法显示F4/80及炎症因子的大量阳性表达(P0.01);使用S1P3抑制剂后,与LPS组比较,心肌损伤减轻免疫组化中巨噬细胞减少(P0.01),炎症因子表达降低(P0.01),BNP mRNA水平降低(P0.01),F4/80以及TNF-α、IL-1β、IL-6的mRNA水平也明显降低(P0.01)。结论抑制巨噬细胞S1P3表达可抑制巨噬细胞的迁移并提示p-Akt/Akt与了这一过程,此外,S1P3抑制剂的干预可有效减轻LPS诱导的心肌损伤。     

Endoscopic and surgical resection of T1a/T1b esophageal neoplasms: A systematic review

AIM: To investigate potential therapeutic recommendations for endoscopic and surgical resection of T1a/ T1b esophageal neoplasms. METHODS: A thorough search of electronic databases MEDLINE, Embase, Pubmed and Cochrane Library, from 1997 up to January 2011 was performed. An analysis was carried out, pooling the effects of outcomes of 4241 patients enrolled in 80 retrospective studies. For comparisons across studies, each reporting on only one endoscopic method, we used a random effects meta-regression of the log-odds of the outcome of treatment in each study. "Neural networks" as a data mining technique was employed in order to establish a prediction model of lymph node status in superficial submucosal esophageal carcinoma. Another data mining technique, the "feature selection and root cause analysis", was used to identify the most impor-tant predictors of local recurrence and metachronous cancer development in endoscopically resected patients, and lymph node positivity in squamous carcinoma (SCC) and adenocarcinoma (ADC) separately in surgically resected patients. RESULTS: Endoscopically resected patients: Low grade dysplasia was observed in 4% of patients, high grade dysplasia in 14.6%, carcinoma in situ in 19%, mucosal cancer in 54%, and submucosal cancer in 16% of patients. There were no significant differences between endoscopic mucosal resection and endoscopic submucosal dissection (ESD) for the following parameters: complications, patients submitted to surgery, positive margins, lymph node positivity, local recurrence and metachronous cancer. With regard to piecemeal resection, ESD performed better since the number of cases was significantly less [coefficient: -7.709438, 95%CI: (-11.03803, -4.380844), P < 0.001]; hence local recurrence rates were significantly lower [coefficient: -4.033528, 95%CI: (-6.151498, -1.915559),P < 0.01]. A higher rate of esophageal stenosis was observed following ESD [coefficient: 7.322266, 95%CI: (3.810146, 10.83439), P < 0.001]. A significantly greater number of SCC pa     

老年2型糖尿病并发ACS患者血清GGT与慢血流-无复流的相关性及其对预后的影响

目的探讨老年2型糖尿病(T2DM)并发急性冠脉综合征(ACS)患者血清γ谷氨酰胺转肽酶(GGT)水平与经皮冠状动脉介入(PCI)治疗术后冠脉慢血流-无复流的相关性及其对预后的影响。方法选取188例诊断为ACS并行急诊PCI的老年T2DM患者,根据TIMI血流分级和校正的TIMI血流帧计数(c TFC)方法评价冠脉血流分为正常血流组(156例)和慢血流-无复流组(32例),分析GGT及其他危险因素与冠脉慢血流-无复流的相关性和主要不良心血管事件(MACE)的发生率。结果慢血流-无复流组的血清GGT水平高于正常血流组[(49±18)U/L vs.(31±13)U/L,P0.01]。相关分析结果显示,血清GGT与冠脉慢血流-无复流呈正相关(r=0.389,P0.01)。血清GGT与PCI术后冠脉慢血流-无复流、住院期间及术后12个月MACE独立相关(分别OR=1.093,95%CI:1.058~1.129,P0.01;OR=1.047,95%CI:1.012~1.082,P0.05及OR=1.058,95%CI:1.028~1.089,P0.01)。结论老年T2DM并发ACS患者血清GGT水平与冠脉慢血流-无复流相关,血清GGT可能是预测冠脉风险的评价指标。     

Endoscopic tools for the diagnosis and evaluation of celiac disease

Celiac disease(CD)is an autoimmune disease of the small bowel induced by ingestion of wheat,rye and barley.Current guidelines indicate histological analysis on at least four duodenal biopsies as the only way to diagnose CD.These indications are based on the conception of the inability of standard endoscopy to make diagnosis of CD and/or to drive biopsy sampling.Over the last years,technology development of endoscopic devices has greatly ameliorated the accuracy of macroscopic evaluation of duodenal villous pattern,increasing the diagnostic power of endoscopy of CD.The aim of this paper is to review the new endoscopic tools and procedures proved to be useful in the diagnosis of CD,such as chromoendoscopy,Fujinon Intelligent Chromo Endoscopy,Narrow Band Imaging,Optical Coherence Tomography,Water-Immersion Technique,confocal laser endomicroscopy,high-resolution magnification endoscopy,capsule endoscopy and I-Scan technology.     

肠道微生态影响动脉粥样硬化发生发展的机制

动脉粥样硬化(AS)不仅是一种炎症性疾病,而且属于一种代谢性疾病。肠道微生态的改变可对AS的发生发展产生双面影响。一方面,肠道菌群紊乱可以通过影响机体的胆碱代谢、氧化应激、炎症反应等机制直接促进AS产生发展,此外,可通过导致AS危险因素肥胖、高脂血症、糖尿病等的产生这些间接机制促AS的进展。另一方面,益生菌及益生元的增加则可有效地降低肠道微生物内毒素产生、增强肠道屏障、减轻机体质量、缓解炎症反应、改善胰岛素抵抗,进而在AS的进展方面发挥重要作用。因此,合理调控机体肠道微生态环境成为AS防治的新型重要手段。     

HBV endemicity in Mexico is associated with HBV genotypes H and G

Hepatitis B virus(HBV)genotypes have distinct genetic and geographic diversity and may be associated with specific clinical characteristics,progression,severity of disease and antiviral response.Herein,we provide an updated overview of the endemicity of HBV genotypes H and G in Mexico.HBV genotype H is predominant among the Mexican population,but not in Central America.Its geographic distribution is related to a typical endemicity among the Mexicans which is characterized by a low hepatitis B surface antigen seroprevalence,apparently due to a rapid resolution of the infection,low viral loads and a high prevalence of occult B infection.During chronic infections,genotype H is detected in mixtures with other HBV genotypes and associated with other co-morbidities,such as obesity,alcoholism and co-infection with hepatitis C virus or human immunodeficiency virus.Hepatocellular carcinoma prevalence is low.Thus,antiviral therapy may differ significantly from the standard guidelines established worldwide.The high prevalence of HBV genotype G in the Americas,especially among the Mexican population,raises new questions regarding its geographic origin that will require further investigation.     

Harnessing the potential of gene editing technology using CRISPR in inflammatory bowel disease

The molecular scalpel of clustered regularly interspersed short palindromic repeats/CRISPR associated protein 9(CRISPR/Cas9) technology may be sharp enough to begin cutting the genes implicated in inflammatory bowel disease(IBD) and consequently decrease the 6.3 billion dollar annual financial healthcare burden in the treatment of IBD. For the past few years CRISPR technology has drastically revolutionized DNA engineering and biomedical research field. We are beginning to see its application in gene manipulation of sickle cell disease,human immunodeficiency virus resistant embryologic twin gene modification and IBD genes such as Gatm(Glycine amidinotransferase, mitochondrial),nucleotide-binding oligomerization domain-containing protein 2, KRT12 and other genes implicated in adaptive immune convergence pathways have been subjected to gene editing, however there are very few publications. Furthermore,since Crohn's disease and ulcerative colitis have shared disease susceptibility and share genetic gene profile, it is paramount and is more advantageous to use CRISPR technology to maximize impact. Although, currently CRISPR does have its limitations due to limited number of specific Cas enzymes, off-target activity,protospacer adjacent motifs and crossfire between different target sites. However,these limitations have given researchers further insight on how to augment and manipulate enzymes to enable precise gene excision and limit crossfire between target sites.     

Current status of endoscopic retrograde cholangiopancreatography in patients with surgically altered anatomy

Endoscopic retrograde cholangiopancreatography(ERCP)in patients with surgically altered anatomy must be performed by a highly experienced endoscopist.The challenges are accessing the afferent limb in different types of reconstruction,cannulating a papilla with a reverse orientation,and performing therapeutic interventions with uncommon endoscopic accessories.The development of endoscopic techniques has led to higher success rates in this group of patients.Device-assisted ERCP is the endoscopic procedure of choice for high success rates in short-limb reconstruction;however,these success rate is lower in long-limb reconstruction.ERCP assisted by endoscopic ultrasonography is now popular because it can be performed independent of the limb length;however,it must be performed by a highly experienced and skilled endoscopist.Stent deployment and small stone removal can be performed immediately after ERCP assisted by endoscopic ultrasonography,but the second session is needed for other difficult procedures such as cholangioscopy-guided electrohydraulic lithotripsy.Laparoscopic-assisted ERCP has an almost 100%success rate in longlimb reconstruction because of the use of a conventional side-view duodenoscope,which is compatible with standard accessories.This requires cooperation between the surgeon and endoscopist and is suitable in urgent situations requiring concomitant cholecystectomy.This review focuses on the advantages,disadvantages,and outcomes of various procedures that are suitable in different situations and reconstruction types.Emerging new techniques and their outcomes are also discussed.     

Abdominal compartment syndrome:Often overlooked conditions in medical intensive care units

Intra-abdominal hypertension(IAH)and abdominal compartment syndrome are well recognized entities among surgical patients.Nevertheless,a number of prospective and retrospective observational studies have shown that IAH is prevalent in about half of the critically ill patients in the medical intensive care units(ICU)and has been widely recognized as an independent risk factor for mortality.It is alarming to note that many members of the critical care team in medical ICU are not aware of the consequences of untreated IAH and the delay in making the diagnosis leads to increased morbidity and mortality.Frequently it is underdiagnosed and undertreated in this patient population.Elevated intraabdominal pressure decreases the blood flow to the kidneys and other abdominal viscera and also results in reduced cardiac output and difficulties in ventilating the patient because of increased intrathoracic pressure.When intraabdominal hypertension is not promptly recognized and treated,it leads to abdominal compartment syndrome,multiorgan dysfunction syndrome and death.Large volume fluid resuscitation is very common in medical ICU patients presenting with sepsis,shock and other inflammatory conditions like pancreatitis and it is one of the major risk factors for the development of intra-abdominal hypertension.This article presents an overview of the epidemiology,definitions,risk factors,pathophysiology and management of IAH and abdominal compartment syndrome in critically ill medical ICU patients.     

Neoadjuvant radiotherapy for rectal cancer management

Thirty per cent of all colorectal tumours develop in the rectum.The location of the rectum within the bony pelvis and its proximity to vital structures presents significant therapeutic challenges when considering neoadjuvant options and surgical interventions.Most patients with early rectal cancer can be adequately managed by surgery alone.However,a significant proportion of patients with rectal cancer present with locally advanced disease and will potentially benefit from down staging prior to surgery.Neoadjuvant therapy involves a variety of options including radiotherapy,chemotherapy used alone or in combination.Neoadjuvant radiotherapy in rectal cancer has been shown to be effective in reducing tumour burden in advance of curative surgery.The gold standard surgical rectal cancer management aims to achieve surgical removal of the tumour and all draining lymph nodes,within an intact mesorectal package,in order to minimise local recurrence.It is critically important that all rectal cancer cases are discussed at a multidisciplinary meeting represented by all relevant specialties.Pre-operative staging including CT thorax,abdomen,pelvis to assess for distal disease and magnetic resonance imaging to assess local involvement is essential.Staging radiology and MDT discussion are integral in identifying patients who require neoadjuvant radiotherapy.While Neoadjuvant radiotherapy is potentially beneficial it may also result in morbidity and thus should be reserved for those patients who are at a high risk of local failure,which includes patients with nodal involvement,extramural venous invasion and threatened circumferential margin.The aim of this review is to discuss the role of neoadjuvant radiotherapy in the management of rectal cancer.     

Quality of life after laparoscopic vs open sphincter-preserving resection for rectal cancer

AIM: To compare quality of life (QoL) outcomes in Chinese patients after curative laparoscopic vs open surgery for rectal cancer. METHODS: Eligible Chinese patients with rectal cancer undergoing curative laparoscopic or open sphincterpreserving resection between July 2006 and July 2008 were enrolled in this prospective study. The QoL outcomes were assessed longitudinally using the validated Chinese versions of the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQCR38 questionnaires before surgery and at 4, 8, and 12 mo after surgery. The QoL scores at the different time points were compared between the laparoscopic and open groups. A higher score on a functional scale indicated better functioning, whereas a higher score on a symptom scale indicated a higher degree of symptoms.RESULTS: Seventy-four patients (49 laparoscopic and 25 open) were enrolled. The two groups of patients were comparable in terms of sociodemographic data, types of surgery, tumor staging, and baseline mean QoL scores. There was no significant decrease from baseline in global QoL for the laparoscopic group at different time points, whereas the global QoL was worse compared to baseline beginning at 4 mo but returned to baseline by 12 mo for the open group (P = 0.019, Friedman test). Compared to the open group, the laparoscopic group had significantly better physical (89.9±1.4 vs 79.2±3.7, P = 0.016), role (85.0±3.4 vs 63.3±6.9, P = 0.005), and cognitive (73.5±3.4 vs 50.7±6.2, P = 0.002) functioning at 8 mo, fewer micturition problems at 4-8 mo (4 mo: 32.3±4.7 vs 54.7±7.1, P = 0.011; 8 mo: 22.8±4.0 vs 40.7±6.9, P = 0.020), and fewer male sexual problems from 8 mo onward (20.0±8.5 vs 76.7±14.5, P = 0.013). At 12 mo after surgery, no significant differences were observed in any functional or symptom scale between the two groups, with the exception of male sexual problems, which remained worse in the open group (29.2±11.3 vs 80.0±9.7, P = 0.026). CONCLUSION: Laparoscopic sphincter-preserving resection for rec     

Loss of BRCA1 expression leads to worse survival in patients with gastric carcinoma

AIM: To investigate the expression deficiency of key molecular markers in the homologous recombination pathway. METHODS: Expression loss of breast cancer type 1 susceptibility protein (BRCA1), ataxia telangiectasia mutated (ATM), ATM-Rad3-related (ATR), mediator of DNA damage checkpoint protein 1 (MDC1) and meiotic recombination 11 (Mre11) were correlated with their clinicopathological parameters in gastric cancer (GC). One hundred and twenty treatment-naive GC samples were formalin-fixed and paraffin-embedded into tissue blocks. Two representative cores from each block were extracted and constructed into tissue microarrays. Expression levels of BRCA1, ATM, ATR, MDC1 and Mre11 were determined using immunohistochemical analysis, and correlated with clinical parameters, including age, gender, Lauren subtype, tumor grades, clinical stage and overall survival.RESULTS: Expression loss of BRCA1, ATM, ATR, MDC1, and Mre11 was found in 21.4%, 20.2%, 21.0%, 11.1% and 4.6%, respectively, of interpretable cases. BRCA1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 8.2% vs 31.7%, P = 0.001), higher tumor grade (Ⅰ/Ⅱ vs Ⅲ, 10.7% vs 20.5;Ⅰ/Ⅱ vs Ⅳ, 10.7% vs 54.5%, P = 0.047) and advanced clinical stage (Ⅰ/Ⅱ vs Ⅲ, 12.9% vs 16.9%;Ⅰ /Ⅱ vs Ⅳ, 12.9% vs 45.5%, P = 0.006). MDC1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 0% vs 19.7%, P = 0.001) and higher tumor grade (Ⅰ/Ⅱ vs Ⅲ, 0% vs 12%;Ⅰ/Ⅱ vs Ⅳ, 0% vs 30.8%, P = 0.012). In addition, the survival time of the patients with expression loss of BRCA1 was significantly shorter than those with positive expression of BRCA1 (2-year survival rate, 32.4% vs 62.8%, P = 0.015). No correlations were found between clinicopathological parameters and expression loss of ATM, ATR and Mre11. CONCLUSION: Our results support the hypothesis that homologous recombination deficiency plays an important role in the progression of gastric carcinoma. Loss of expression of BRCA1 and     

Assessment of chronic radiation proctopathy and radiofrequency ablation treatment follow-up with optical coherence tomography angiography: A pilot study

BACKGROUND Chronic radiation proctopathy(CRP) occurs as a result of pelvic radiation therapy and is associated with formation of abnormal vasculature that may lead to persistent rectal bleeding. While incidence is declining due to refinement of radiation delivery techniques, CRP remains one of the major complications of pelvic radiation therapy and significantly affects patient quality of life.Radiofrequency ablation(RFA) is an emerging treatment modality for eradicating abnormal vasculature associated with CRP. However, questions remain regarding CRP pathophysiology and optimal disease management.AIM To study feasibility of optical coherence tomography angiography(OCTA) for investigating subsurface vascular alterations in CRP and response to RFA treatment.METHODS Two patients with normal rectum and 8 patients referred for, or undergoing endoscopic RFA treatment for CRP were imaged with a prototype ultrahighspeed optical coherence tomography(OCT) system over 15 OCT/colonoscopy visits(2 normal patients, 5 RFA-na?ve patients, 8 RFA-follow-up visits). OCT and OCTA was performed by placing the OCT catheter onto the dentate line and rectum without endoscopic guidance. OCTA enabled depth-resolved microvasculature imaging using motion contrast from flowing blood, withoutrequiring injected dyes. OCTA features of normal and abnormal microvasculature were assessed in the mucosa and submucosa. Blinded reading of OCTA images was performed to assess the association of abnormal rectal microvasculature with CRP and RFA treatment, and rectal telangiectasia density endoscopic scoring.RESULTS OCTA/OCT images are intrinsically co-registered and enabled depth-resolved visualization of microvasculature in the mucosa and submucosa. OCTA visualized normal vascular patterns with regular honeycomb patterns vs abnormal vasculature with distorted honeycomb patterns and ectatic/tortuous microvasculature in the rectal mucosa. Normal arterioles and venules < 200 μm in diameter versus abnormal heterogenous enlarged arterioles and venules > 200μm in diameter were visualized in the rectal submucosa. Abnormal mucosal vasculature occurred in 0 of 2 normal patients and 3 of 5 RFA-na?ve patients,while abnormal submucosal vasculature occurred more often, in 1 of 2 normal patients and 5 of 5 RFA-na?ve patients. After RFA treatment, vascular abnormalities decreased, with abnormal mucosal vasculature observed in 0 of 8 RFA-follow-up visits and abnormal submucosal vasculature observed in only and 2 of 8 RFA-follow-up visits.CONCLUSION OCTA visualizes depth-resolved microvascular abnormalities in CRP, allowing assessment of superficial features which are endoscopically visible as well as deeper vasculature which cannot be seen endoscopically. OCTA/OCT of the rectum can be performed in conjunction with, or independently from endoscopy.Further studies are warranted to investigate if OCTA/OCT can elucidate pathophysiology of CRP or improve management.     

PNPLA3 I148M polymorphism and progressive liver disease

The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.     

Endoscopic Kyoto classification of Helicobacter pylori infection and gastric cancer risk diagnosis

Recent advances in endoscopic technology allow detailed observation of the gastric mucosa.Today,endoscopy is used in the diagnosis of gastritis to determine the presence/absence of Helicobacter pylori(H.pylori)infection and evaluate gastric cancer risk.In 2013,the Japan Gastroenterological Endoscopy Society advocated the Kyoto classification,a new grading system for endoscopic gastritis.The Kyoto classification organized endoscopic findings related to H.pylori infection.The Kyoto classification score is the sum of scores for five endoscopic findings(atrophy,intestinal metaplasia,enlarged folds,nodularity,and diffuse redness with or without regular arrangement of collecting venules)and ranges from 0 to 8.Atrophy,intestinal metaplasia,enlarged folds,and nodularity contribute to gastric cancer risk.Diffuse redness and regular arrangement of collecting venules are related to H.pylori infection status.In subjects without a history of H.pylori eradication,the infection rates in those with Kyoto scores of 0,1,and≥2 were 1.5%,45%,and 82%,respectively.A Kyoto classification score of 0 indicates no H.pylori infection.A Kyoto classification score of 2 or more indicates H.pylori infection.Kyoto classification scores of patients with and without gastric cancer were 4.8 and 3.8,respectively.A Kyoto classification score of 4 or more might indicate gastric cancer risk.     

Totally laparoscopic left hepatectomy using the Torsional Ultrasonic Scalpel

Minimal invasive techniques have allowed for major surgical advances.We report our initial experience of performing total laparoscopic left hepatectomy(segmentsⅡ-Ⅳ)with the Lotus(laparoscopic operation by torsional ultrasound)Ultrasonic Scalpel.The perioperative and postoperative courses of the young female patient were uneventful and she is in a good general condition without complaints 18 mo after surgery.To the best of our knowledge,this is the first total laparoscopic hemihepatectomy to be performed in Greece,as well as the first laparoscopic liver resection using Lotus shears.     

Contribution of pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency

The objective of this study was to analyze the current evidence for the use of pancreatic enzyme replacement therapy (PERT) in affecting survival and quality of life in patients with pancreatic exocrine insufficiency (PEI). Systematic searches of the literature were performed using the PubMed database. Articles were selected for inclusion if they reported findings from trials assessing the effects of PERT on quality of life, survival, malabsorption, growth parameters (such as height, body weight and body mass index), or gastrointestinal symptoms (such as abdominal pain, stool consistency and flatulence). PERT improved PEI-related malabsorption and weight maintenance in patients with cystic fibrosis, chronic pancreatitis, pancreatic cancer, and post-surgical states. In patients with chronic pancreatitis, PERT improved PEI-related symptoms and quality of life measures. Several small retrospective studies have also suggested that PERT may have a positive impact on survival, but long-term studies assessing this effect were not identified. PERT is effective for treating malnutrition and supporting weight maintenance, and it is associated with improved quality of life and possibly with enhanced survival in patients with PEI. However, there is evidence that not all patients with PEI receive adequate PERT. Future work should aim to assess the long-term effects of PERT on the survival of patients with PEI.     

Post-translational modifications of hepatitis C viral proteins and their biological significance

Replication of hepatitis C virus(HCV)depends on the interaction of viral proteins with various host cellular proteins and signalling pathways.Similar to cellular proteins,post-translational modifications(PTMs)of HCV proteins are essential for proper protein function and regulation,thus,directly affecting viral life cycle and the generation of infectious virus particles.Cleavage of the HCV polyprotein by cellular and viral proteases into more than 10 proteins represents an early protein modification step after translation of the HCV positivestranded RNA genome.The key modifications include the regulated intramembranous proteolytic cleavage of core protein,disulfide bond formation of core,glycosylation of HCV envelope proteins E1 and E2,methylation of nonstructural protein 3(NS3),biotinylation of NS4A,ubiquitination of NS5B and phosphorylation of core and NS5B.Other modifications like ubiquitination of core and palmitoylation of core and NS4B proteins have been reported as well.For some modifications such as phosphorylation of NS3 and NS5A and acetylation of NS3,we have limited understanding of their effects on HCV replication and pathogenesis while the impact of other modifications is far from clear.In this review,we summarize the available information on PTMs of HCV proteins and discuss their relevance to HCV replication and pathogenesis.     

Hepatoprotective actions of melatonin: possible mediation by melatonin receptors

Melatonin,the hormone of darkness and messenger of the photoperiod,is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone’s intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo,and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis,hemorrhagic shock,ischemia/reperfusion,and in numerous models of toxic liver injury. Melatonin’s influence on hepatic antioxidant enzymes and other potentially relevant pathways,such as nitric oxide signaling,hepatic cytokine and heat shock protein expression,are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection,this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.     

Separate calculation of DW-MRI in assessing therapeutic effect in liver tumors in rats

AIM:To explore whether the antitumor effect of a vascular disrupting agent(VDA)would be enhanced by combining with an antiangiogenic agent,and whether such synergistic effects can be effectively evaluated with separate calculation of diffusion weighted magnetic resonance imaging(DW-MRI).METHODS:Thirty-seven rats with implanted liver tumors were randomized into the following three groups:(1)ZD6126,a kind of VDA;(2)ZDTHA,ZD6126 in combination with an antiangiogenic,thalidomide;and(3)control.Morphological DW-MRI were performed and quantified before,4 h and 2 d after treatment.The apparent diffusion coefficient(ADC)values were calculated separately for low b values(ADC low),high b values(ADC high)and all b values(ADC all).The tissue perfusion contribution,ADC perf,was calculated as ADC low-ADC high.Imaging findings were finally verified by histopathology.RESULTS:The combination therapy with ZDTHA significantly delayed tumor growth due to synergistic effects by inducing cumulative tumor necrosis.In addition to delaying tumor growth,ZDTHA caused tumor necrosis in an additive manner,which was verified by HE staining.Although both ADC high and ADC all in the ZD6126and ZDTHA groups were significantly higher compared to those in the control group on day 2,the entire tumor ADC high of ZDTHA was even higher than that of ZD6126,but the significant difference was not observed for ADCall between ZDTHA and ZD6126.This indicated that the perfusion insensitive ADC high values calculated from high b value images performed significantly better than ADC all for the monitoring of tumor necrosis on day 2.The perfusion sensitive ADC perf derived from ADC low by excluding high b value effects could better reflect the reduction of blood flow due to the vessel shutdown induced by ZD6126,compared to the ADC low at 4 h.The ADC perf could provide valuable perfusion information from DW-MRI data.CONCLUSION:The separate calculation of ADC is more useful than conventional averaged ADC in evaluating the efficacy of combination therapy with ZD6126