Role of exosomal circular RNAs as microRNA sponges and potential targeting for suppressing hepatocellular carcinoma growth and progression

In this editorial,we comment on the article by Lyu et al published in the recent issue of the World Journal of Gastroenterology(2023;2219-2840).Hepatocellular carcinoma(HCC)is a frequently encountered and highly aggressive primary liver cancer,which remains the third-commonest cause of cancer-related death despite the current therapeutic modalities.There is urgency in developing novel thera-peutic approaches,such as by manipulating extracellular vesicles,which con-stitute a highly heterogeneous nanoparticle population that contains various cargoes.These cargoes have a pivotal role in cell-to-cell communication and can modify the functional level of the recipient cells via their uptake by other recipient cells.Exosomal non-coding RNAs have particular evolving significance in HCC,such as circular RNAs,which have been found differentially expressed in normal hepatic and HCC tissues.The aberrations in their expression levels have a key role in the HCC development and progression and the overall prognosis.In this editorial,we will shed light on the emerging role of exosomal circular RNAs in HCC development and progression,focusing on the oncogenic or potentially tumor suppressive effect of mesenchymal stem cells-derived exosomal non-coding RNAs.

Endoscopic management of benign biliary strictures:Looking for the best stent to place

Benign biliary strictures(BBS)might occur due to different pancreaticobiliary conditions.The etiology and location of biliary strictures are responsible of a wide array of clinical manifestations.The endoscopic approach endoscopic retrograde cholangiopancreatography represents the first-line treatment for BBS,considering interventional radiology and surgery when endoscopic treatment fails or it is not suitable.The purpose of this review is to provide an overview of possible endoscopic treatments for the optimal management of this subset of patients.

Characterization of functional biliary pain and dyspeptic symptoms in patients with sphincter of Oddi dysfunction:Effect of papillotomy

AIM： To characterize functional biliary pain and other gastrointestinal （GI） symptoms in postcholecystectomy syndrome （PCS） patients with and without sphincter of Oddi dysfunction （SOD） proved by endoscopic sphincter of Oddi manometry （ESOM）, and to assess the postendoscopic sphincterotomy （EST） outcome. METHODS： We prospectively investigated 85 cholecystectomized patients referred for ERCP because of PCS and suspected SOD. On admission, all patients completed our questionnaire. Physical examination, laboratory tests, abdominal ultrasound, quantitative hepatobiliary scintigraphy （QHBS）, and ERCP were performed in all patients. Based on clinical and ERCP findings 15 patients had unexpected bile duct stone disease and 15 patients had SOD biliary type Ⅰ. ESOM demonstrated an elevated basal pressure in 25 patients with SOD biliary-type Ⅲ. In the remaining 30 cholecystectomized patients without SOD, the liver function tests, ERCP, QHBS and ESOM were all normal. As a control group, 30 ‘asymptomatic＇ cholecystectomized volunteers （attended to our hospital for general cardiovascular screening） completed our questionnaire, which is consisted of 50 separate questions on GI symptoms and abdominal pain characteristics. Severity of the abdominal pain （frequency and intensity） was assessed with a visual analogue scale （VAS）. In 40 of 80 patients having definite SOD （i.e. patients with SOD biliary type Ⅰ and those with elevated SO basal pressure on ESOM）, an EST was performed just afl：er ERCP. In these patients repeated questionnaires were filled at each follow-up visit （at 3 and 6 too） and a second look QHBS was performed 3 mo after the EST to assess the functional response to EST. RESULTS： The analysis of characteristics of the abdominal pain demonstrated that patients with common bile duct stone and definite SOD had a significantly higher score of symptomatic agreement with previously determined biliary-like pain features than patient groups of PCS without SOD and controls. In contrary, no significant differences were found when the pain severity scores were compared in different groups of PCS patients. In patients with definite SOD, EST induced a significant acceleration of the transpapillary bile flow; and based on the comparison of VASs obtained from the pre-and post-EST questionnaires, the severity scores of abdominal pain were significantly improved, however, only 15 of 35 （43%） patients became completely pain free. Post-EST severity of abdominal pain by VASs was significantly higher in patients with predominant dyspepsia at initial presentation as compared to those without dyspeptic symptoms. CONCLUSION： Persistent GI symptoms and general patient dissatisfaction is a rather common finding after EST in patients with SOD, and correlated with the presence of predominant dyspeptic symptoms at the initial presentation, but does not depend on the technical and functional success of EST.

High miR-196a levels promote the oncogenic phenotype of colorectal cancer cells

AIM： To analyze the relevance of the microRNA miR-196a for colorectal oncogenesis.METHODS： The impact of miR-196a on the restriction targets HoxA7, HoxBS, HoxC8 and HoxD8 was analyzed by reverse transcription polymerase chain reaction（RT-PCR） after transient transfection of SW480 cancer cells. The miR-196a transcription profile in colorectalcancer samples, mucosa samples and diverse cancercell lines was quantified by RT-PCR. Transiently miR-196a-transfected colorectal cancer cells were used for diverse functional assays in vitro and for a xenograft lung metastasis model in vivo.RESULTS： HoxA7, HoxB8, HoxC8 and HoxD8 wererestricted by miR-196a in a dose-dependent andgene-specific manner. High levels of miR-196aactivated the AKT signaling pathway as indicated byincreased phosphorylation of AKT. In addition, highlevels of miR-196a promoted cancer cell detachment,migration, invasion and chemosensitivity towardsplatin derivatives but did not impact on proliferationor apoptosis. Furthermore, miR-196a increased thedevelopment of lung metastases in mice after tail veininjection.

Effects of octreotide on acute necrotizing pancreatitis in rabbits

AIM:To assess the role of oxygen-derived free radicals and cytokines in the pathogenesis of taurocholic acid-induced acute pancreatitis,and to evaluate the preventive effects of octreotide towards the development of acute pancreatitis. METHODS:Acute pancreatitis was induced in male New Zealand white rabbits by retrograde injection of 0.8 mL/kg·b.m,of 50 g/L sodium taurocholate (NaTC) in the pancreatic duct.Sham- operated animals served as control.Octreotide i mg/kg·b.m. was administered subcutaneously before the induction of pancreatitis.Blood was taken from the jugular vein before and at 1,3,6,12 and 24 h after pancreatitis induction. Serum activities of amylase,IL-6 and TNF-α and levels of malonyl dialdehyde (MDA),glutathione (GSH),glutathione peroxidase (GPx),catalase and superoxide dismutase (Mn-, Cu-,and Zn-SOD) in pancreatic tissue were measured. RESULTS:Serum TNF-α and IL-6 levels increased significantly 3 h after the onset of pancreatitis,and then returned to control level.The tissue concentration of MDA was significantly elevated at 24 h,while the GSH level and GP-x,catalase,Mn-SOD,Cu-,Zn-SOD activities were all significantly decreased in animals with pancreatitis as compared to the control.Octreotide pretreatmnent significantly reversed the changes in cytokines and reactive oxygen metabolites.Octreotide treatment did not alter the serum amylase activity and did not have any beneficial effects on the development of histopathological changes. CONCLUSION:Oxygen-derived free radicals and proinflammatory cytokines are generated at an early stage of NaTc-induced acute pancreatitis in rabbits.Prophylactic octreotide treatment can prevent release of cytokines and generation of reactive oxygen metabolites,but does not have any beneficial effects on the development of necrotizing pancreatitis.

A candidate targeting molecule of insulin-like growth factor-Ⅰ receptor for gastrointestinal cancers

Advances in molecular research in cancer have brought new therapeutic strategies into clinical usage.One new group of targets is tyrosine kinase receptors,which can be treated by several strategies,including small molecule tyrosine kinase inhibitors(TKIs) and monoclonal antibodies(mAbs).Aberrant activation of growth factors/receptors and their signal pathways are required for malignant transformation and progression in gastrointestinal(GI) carcinomas.The concept of targeting specif ic carcinogenic receptors has been validated by successful clinical application of many new drugs.Type I insulin-like growth factor(IGF) receptor(IGF-IR) signaling potently stimulates tumor progression and cellular differentiation,and is a promising new molecular target in human malignancies.In this review,we focus on this promising therapeutic target,IGF-IR.The IGF/IGF-IR axis is an important modifier of tumor cell proliferation,survival,growth,and treatment sensitivity in many malignant diseases,including human GI cancers.Preclinical studies demonstrated that downregulation of IGF-IR signals reversed the neoplastic phenotype and sensitized cells to anticancer treatments.These results were mainly obtained through our strategy of adenoviruses expressing dominant negative IGF-IR(IGF-IR/dn) against gastrointestinal cancers,including esophagus,stomach,colon,and pancreas.We also summarize a variety of strategies to interrupt the IGFs/IGF-IR axis and their preclinical experiences.Several mAbs and TKIs targeting IGF-IR have entered clinical trials,and early results have suggested that these agents have generally acceptable safety profiles as single agents.We summarize the advantages and disadvantages of each strategy and discuss the merits/demerits of dual targeting of IGF-IR and other growth factor receptors,including Her2 and the insulin receptor,as well as other alternatives and possible drug combinations.Thus,IGF-IR might be a candidate for a molecular therapeutic target in human GI carcinomas.

Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer

AIM： To clarify alterations of Dickkopfs （Dkks） and Kremen2 （Krm2） in gastrointestinal cancer. METHODS： We investigated the expression profiles and epigenetic alterations of Dkks and Krm2 genes in gastrointestinal cancer using RT-PCR, tissue microarray analysis, and methylation specific PCR （MSP）. Cancer cells were treated with the demethylating agent and/or histone deacetylase inhibitor. WST-8 assays and/n y/tro invasion assays after treatment with specific siRNA for those genes were performed. RESULTS： Dkks and Krm2 expression levels were reduced in a certain subset of the gastrointestinal cancer cell lines and cancer tissues. This was correlated with promoter hypermethylation. There were significant correlations between Dkks over-expression levels and beta-catenin over-expression in colorectal cancer. In colorectal cancers with beta-catenin over-expression, Dkk-1 expression levels were significantly lower in those with lymph node metastases than in those without. Down-regulation of Dkks expression by siRNA resulted in a significant increase in cancer cell growth and invasiveness in vitro.CONCLUSION： Down-regulation of the Dkks associated to promoter hypermethylation appears to be frequently involved in gastrointestinal tumorigenesis.

Multidisciplinary management of gastric and gastroesophageal cancers

Carcinomas of the stomach and gastroesophageal junction are among the five top leading cancer types worldwide. In spite of radical surgical R0 resections being the basis of cure of gastric cancer, surgery alone provides long-term survival in only 30% of patients with advanced International Union Against Cancer （UICC） stages in Western countries because of the high risk of recurrence and metachronous metastases. However, recent large phase-Ⅲ studies improved the diagnostic and therapeutic options in gastric cancers, indicating a more multidisciplinary management of the disease. Multimodal strategies combining different neoadjuvant and/or adjuvant protocols have clearly improved the gastric cancer prognosis when combined with surgery with curative intention. In particular, the perioperative （neoadjuvant, adjuvant） chemotherapy is now a well-established new standard of care for advanced tumors. Adjuvant therapy alone should be carefully discussed after surgical resection, mainly in individual patients with large lymph node positive tumors when neoadjuvant therapy could not be done. The palliative treatment options have also been remarkably improved with new chemotherapeutic agents and will further be enhanced with targeted therapies such as different monoclonal antibodies. This article reviews the most relevant literature on the multidisciplinary management of gastric and gastroesophageal cancer, and discusses future strategies toimprove Iocoregional failures.

Noninvasive estimation of liver fibrosis and response to interferon therapy by a serum fibrogenesis marker, YKL-40, in patients with HCV-associated liver disease

AIM: To evaluate the clinical utility of serum fibrosis markers, including YKL-40, in patients with HCV-associated liver disease. METHODS: A total of 109 patients with HCV-associated liver disease were enrolled. We measured serum type IV collagen, amino-terminal peptide of type III procollagen (PIIIP), hyaluronic acid (HA), YKL-40 levels and biochemical. Parameters by RIA or ELISA. Eighty-eight patients underwent liver biopsy, and 67 of 109 patients received interferon (IFN) therapy. We also investigated the relationship between the concentrations of serum fibrosis markers and histological fibrosis scores (METAVIR), and evaluated the changes of the levels of fibrosis markers before and after the IFN therapy. RESULTS: The increase in serum levels of all markers, particularly HA, was correlated with the progression of liver fibrosis (for type IV collagen, F= 9.076, P<0.0001; for PIIIP, F= 9.636, P<0.0001; for HA, F=13.128, P<0.0001; and for YKL-40, F= 8.016, P<0.0001). YKL-40 had strong correlation with HA (r= 0.536, P<0.0001). Based on the receiver operating curve (ROC), the ability of serum HA exceeded the abilities of other serum markers to determine fibrosis score 4 from fibrosis score 0-3 (AUC = 0.854). While YKL-40 was superior to other fibrosis markers for predicting severe fibrosis (F2-F4) from mild fibrosis (FO-F1) (YKL-40, AUC = 0.809; HA, AUC = 0.805). After IFN therapy, only YKL-40 values significantly decreased not only in the responder group, but also in the nonresponder group (P = 0.03). CONCLUSION: YKL-40 may be a useful non-invasive serum marker to estimate the degree of liver fibrosis and to evaluate the efficacy of IFN therapies in patients with HCV-associated liver disease.

Clinical impact of microbiome in patients with decompensated cirrhosis

Cirrhosis is an increasing cause of morbidity and mortality. Recent studies are trying to clarify the role of microbiome in clinical exacerbation of patients with decompensated cirrhosis. Nowadays, it is accepted that patients with cirrhosis have altered salivary and enteric microbiome, characterized by the presence of dysbiosis. This altered microbiome along with small bowel bacterial overgrowth, through translocation across the gut, is associated with the development of decompensating complications. Studies have analyzed the correlation of certain bacterial families with the development of hepatic encephalopathy in cirrhotics. In general, stool and saliva dysbiosis with reduction of autochthonous bacteria in patients with cirrhosis incites changes in bacterial defenses and higher risk for bacterial infections, such as spontaneous bacterial peritonitis, and sepsis. Gut microbiome has even been associated with oncogenic pathways and under circumstances might promote the development of hepatocarcinogenesis. Lately, the existence of the oral-gutliver axis has been related with the development of decompensating events. This link between the liver and the oral cavity could be via the gut through impaired intestinal permeability that allows direct translocation of bacteria from the oral cavity to the systemic circulation. Overall, the contribution of the microbiome to pathogenesis becomes more pronounced with progressive disease and therefore may represent an important therapeutic target in the management of cirrhosis.

Functional expression of a proliferation-related ligand in hepatocellular carcinoma and its implications for neovascularization

AIM： To detect the expression of a proliferation-related ligand on human hepatocellular carcinoma （HCC） cell lines （SK-Hepl, HLE and HepG2） and in culture medium. METHODS： APRIL expression was analyzed by Western blotting in HCC cell lines. Effects of APRIL to cell count and angiogenesis were analyzed, too. RESULTS： Recombinant human APRIL （rhAPRIL） increased cell viability of HepG2 cells and, in HUVEC, rhAPRIL provided slight tolerance to cell death from serum starvation. Soluble APRIL （sAPRIL） from HLE cells increased after serum starvation, but did not change in SK-Hepl or HepG2 cells. These cells showed down-regulation of VEGF after incubation with anti-APRIL antibody. Furthermore, culture medium from the HCC cells treated with anti-APRIL antibody treatment inhibited tube formation of HUVECs. CONCLUSION： Functional expression of APRIL might contribute to neovascularization via an upregulation of VEGF in HCC.

Diagnostic evaluation of acute pancreatitis in two patients with hypertriglyceridemia

We present two diagnostically challenging cases of acute pancreatitis with hypertriglyceridemia accompanied with chylomicronemia caused with a deficiency of lipoprotein lipase and with the presence of type Ⅴ hyperlipidemia. Both cases suffered from acute abdomen following the ingestion of fatty food and revealed the increase in parameters of inflammation without significant elevation of serum amylase levels.The imaging examination of ultrasonography could not detect significant findings of acute pancreatitis and a computer tomography scan eventually confirmed the findings of acute pancreatitis.Both cases responded to a low fat diet and administration of a cholecystokinin receptor antagonist,exhibiting a relief of abdominal symptoms.As in the present cases with acute abdomen following the ingestion of fatty food,the identification of serum hypertriglyceridemia and an abdominal computer tomography scan might be useful in establishing the diagnosis of acute pancreatitis and in developing the therapeutic regimen,when hypertriglyceridemia interferes with the evaluation of pancreatic enzyme activities and ultrasound examination provides poor pancreatic visualization.

Biliary drainage strategy of unresectable malignant hilar strictures by computed tomography volumetry

AIM:To identify criteria for predicting successful drainage of unresectable malignant hilar biliary strictures(UMHBS) because no ideal strategy currently exists.METHODS:We examined 78 patients with UMHBS who underwent biliary drainage.Drainage was considered effective when the serum bilirubin level decreased by ≥ 50% from the value before stent placement within 2 wk after drainage, without additional intervention.Complications that occurred within 7 d after stent placement were considered as early complications.Before drainage, the liver volume of each section(lateral and medial sections of the left liver and anterior and posterior sections of the right liver) was measured using computed tomography(CT) volumetry.Drained liver volume was calculated based on the volume of each liver section and the type of bile duct stricture(according to the Bismuth classification).Tumor volume, which was calculated by using CT volumetry, was excluded from the volume of each section.Receiver operating characteristic(ROC) analysis was performed to identify the optimal cutoff values for drained liver volume.In addition, factors associated with the effectiveness of drainage and early complications were evaluated.RESULTS:Multivariate analysis showed that drained liver volume [odds ratio(OR) = 2.92, 95%CI:1.648-5.197; P < 0.001] and impaired liver function(with decompensated liver cirrhosis)(OR = 0.06, 95%CI:0.009-0.426; P = 0.005) were independent factors contributing to the effectiveness of drainage.ROC analysis for effective drainage showed cutoff values of 33% of liver volume for patients with preserved liver function(with normal liver or compensated livercirrhosis)and 50%for patients with impaired liver function(with decompensated liver cirrhosis).The sensitivity and specificity of these cutoff values were82%and 80%for preserved liver function,and 100%and 67%for impaired liver function,respectively.Among patients who met these criteria,the rate of effective drainage among those with preserved liver function and impaired liver function was 90%and 80%,respectively.The rates of effective drainage in both groups were significantly higher than in those who did not fulfill these criteria(P<0.001 and P=0.02,respectively).Drainage-associated cholangitis occurred in 9 patients(12%).A smaller drained liver volume was associated with drainage-associated cholangitis(P<0.01).CONCLUSION:Liver volume drainage≥33%in patients with preserved liver function and≥50%in patients with impaired liver function correlates with effective biliary drainage in UMHBS.

Association of glypican-3 expression with growth signaling molecules in hepatocellular carcinoma

AIM:To clarify the association of glypican-3(GPC3)expression with Wnt and other growth signaling molecules in hepatocellular carcinoma(HCC). METHODS:Expression of GPC3,Wnt,matrix metalloproteinases(MMPs),sulfatase(SULF)1,SULF2,and other growth signaling molecules was analyzed in HCC cell lines and tissue samples by real-time reverse transcriptionpolymerase chain reaction,immunoblotting,and/or immunostaining.Expression of various genes in GPC3 siRNA-transfected HCC cells was analyzed. RESULTS:GPC3 was overexpressed in most HCCs at mRNA and protein levels and its serum levels weresignificantly higher in patients with HCC than in non- HCC subjects(P<0.05).Altered expressions of various MMPs and growth signaling molecules,some of which were correlated with GPC3 expression,were observed in HCCs.Down-regulation of GPC3 expression by siRNA in GPC3-overexpressing HCC cell lines resulted in a significant decrease in expressions of MMP2,MMP14,fibroblast growth factor receptor 1,insulin-like growth factor 1 receptor.GPC3 expression was significantly correlated with nuclear/cytoplasmic localization ofβ-catenin. CONCLUSION:These results suggest that GPC3,in conjunction with MMPs and growth signaling molecules, might play an important role in the progression of HCC.

Gender and metabolic differences of gallstone diseases

AIM： To investigate the risk factors for gallstone disease in the general population of Chengdu, China. METHODS： This study was conducted at the West China Hospital. Subjects who received a physical examination at this hospital between January and December 2007 were included. Body mass index, blood pressure, fasting plasma glucose, serum lipid and lipoproteins concentrations were analyzed. Gallstone disease was diagnosed by ultrasound or on the basis of a history of cholecystectomy because of gallstone disease. Unconditional logistic regression analysis was used to investigate the risk factors for gallstone disease, and the Chi-square test was used to analyze differences in the incidence of metabolic disorders between subjects with and without gallstone disease. RESULTS： A total of 3573 people were included, 10.7% （384/3573） of whom had gallstone diseases. Multiple logistic regression analysis indicated that the incidence of gallstone disease in subjects aged 40-64 or ≥65 years was significantly different from that in those aged 18-39 years （P 〈 0.05）; the incidence was higher in women than in men （P 〈 0.05）. In men,a high level of fasting plasma glucose was obvious in gallstone disease （P 〈 0.05）, and in women, hypertriglyceridemia or obesity were significant in gallstone disease （P 〈 0.05）. CONCLUSION： We assume that age and sex are profoundly associated with the incidence of gallstone disease; the metabolic risk factors for gallstone disease were different between men and women.

Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers

AIM: To clarify the expression and role of Ephrin receptor A4 (EphA4) in gastric cancer in relation to clinicopathological characteristics and the expression of fibroblast growth factor receptor 1 (FGFR1) and ephrin ligands. METHODS: Eleven gastric carcinoma cell lines, 24 paired surgical fresh specimens of gastric adenocarcinoma and adjacent nontumor tissue, 74 conventional formalin-fixed, paraffin-embedded tumor specimens, and 55 specimens spotted on tissue microarray (TMA) were analyzed. Reverse transcription-PCR (RT-PCR), real-time RT-PCR, immunohistochemistry, and cell growth assays were performed. RESULTS: Overexpression of EphA4 mRNA expres-sion was observed in 8 (73%) of 11 gastric cancer cell lines and 10 (42%) of 24 gastric cancer tissues. Over-expression of EphA4, analyzed by immunohistochemistry, was observed in 62 (48%) of 129 gastric cancer tissues. EphA4 overexpression, at the protein level, was significantly associated with depth of invasion and recurrence. EphA4 overexpression was also correlated with FGFR1 overexpression. Patients with EphA4-positive cancer had significantly shorter overall survival periods than did those with EphA4-negative cancer (P = 0.0008). The mRNAs for ephrin ligands were coexpressed in various combinations in gastric cancer cell lines and cancer tissues. Downregulation of EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. CONCLUSION: Our results suggest that overexpres-sion of EphA4 plays a role in gastric cancer.

Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease

AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease. However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type VI collagen 7S domain and hyaluronic acid. METHODS: One hundred and twelve patients with histologically proven NAFLD were studied. RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type VI collagen 75 domain ≥5.0 ng/mL, hyaluronic acid ≥43 ng/mL. Both markers had a high positive predictive value: type VI collagen 7S domain, 86% and hyaluronic acid, 92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type VI collagen 7S domain (≥5.0 ng/mL), 84% and hyaluronic acid (≥50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis. CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis.

Effects of medicinal plants on Alzheimer＇s disease and memory deficits

Alzheimer＇s disease is an age-related neurodegenerative disorder characterized by memory deficits. Various studies have been carried out to find therapeutic approaches for Alzheimer＇s disease. However, the proper treatment option is still not available. There is no cure for Alzheimer＇s disease, but symptomatic treatment may improve the memory and other dementia related problems. Traditional medicine is practiced world- wide as memory enhancer since ancient times. Natural therapy including herbs and medicinal plants has been used in the treatment of memory deficits such as dementia, amnesia, as well as Alzheimer＇s disease since a long time. Medicinal plants have been used in different systems of medicine, particularly Unani system of medicines and exhibited their powerful roles in the management and cure of memory disorders. Most of herbs and plants have been chemically evaluated and their efficacy has also been proven in clinical trials. However, the underlying mechanisms of actions are still on the way. In this paper, we have reviewed the role of different medicinal plants that play an important role in the treatment of Alzheimer＇s disease and memory deficits using conventional herbal therapy.

Efficacy of balloon-occluded retrograde transvenous obliteration, percutaneous transhepatic obliteration and combined techniques for the management of gastric fundal varices

AIM： To evaluate the effect of three interventional treatments involving transvenous obliteration for the treatment of gastric varices, and to compare the efficacy and adverse effects of these methods, METHODS： From 1995 to 2004, 93 patients with gastric fundal varices underwent interventional radiologic embolotherapy at our hospital. Of the 93 patients, 75 were treated with the balloon-occluded retrograde transvenous obliteration （BRTO） procedure; 8 were with the percutaneous transhepatic obliteration （PTO） procedure; and 10 were with the combined BRTO and PTO therapy. A follow-up evaluation examined the rates of survival, recurrence and rebleeding of the gastric varices, worsening of esophageal varices and complications in each group. RESULTS： The BRTO, PTO, and combined therapy were technically successful in 81% （75/93）, 44% （8/18）, and 100% （10/10） patients, respectively. Recurrence of gastric varices was found in 3 patients in the BRTO group and in 3 patients in the PTO group. Rebleeding was observed in 1 patient in the BRTO group and in 1 patient in the PTO group. The 1- and 3-year survival rates were 98% and 87% in the patients without hepatocellular carcinoma （HCC） in the BRTO group, 100% and 100% in the PTO group, and 90% and 75% in the combined therapy group, respectively. CONCLUSION： Combined BRTO and PTO therapy may rescue cases with uncontrollable gastric fundal varices that remained even after treatment with BRTO and/or PTO, though there were limitations of our study, including retrospective nature and discrepancy in sample size between the BRTO, PTO and combined therapy groups.

Evaluation of the biliary tract in patients with functional biliary symptoms

The aim of this paper was to describe functional biliary syndromes and methods for evaluation of the biliary tract in these patients. Functional biliary symptoms can be defined as biliary symptoms without demonstrable organic substrate. Two main syndromes exist： Gallbladder dysfunction and sphincter of Oddi dysfunction. The most important investigative tools are cholescintigraphy and endoscopic sphincter of Oddi manometry. In gallbladder dysfunction a scintigraphic gallbladder ejection fraction below 35% can select patients who will benefit from cholecystectomy. Endoscopic sphincter of Oddi manometry is considered the gold standard in sphincter of Oddi dysfunction but recent development in scintigraphic methods is about to change this. Thus, calculation of hilum-to-duodenum transit time and duodenal appearance time on cholescintigraphy have proven useful in these patients. In conclusion, ambient methods can diagnose functional biliary syndromes. However, there are still a number of issues where further knowledge is needed. Probably the next step forward will be in the area of sensory testing and impedance planimetric methods.