Gastroenterology and Hepatology from Bed to Bench

Aim: This review provides a comprehensive overview of more than 100 of the most cited studies in general medical journals and evaluates whether citations predict the quality of a scientific article.

Background: The number of citations is commonly used as a measure of the quality and impact of a scientific article. However, it is often criticised that the number of citations is in fact a poor indicator of the true quality, as it can be influenced by different factors such as current trends.

Methods: This review was conducted in line with the PRISMA guidelines. The Journal Citation Report (JCR) within Incites allowed the evaluation and comparison of articles, published in general medical journals, using far-reaching citation data drawn from scholarly and technical journals and conference proceedings. All steps of the review were performed in duplicate and conflicts were resolved through consensus.

Results: The 100 most cited articles published from 1963 until the end of 2018 were identified. The number of citations ranged from 4012 to 31853. Most of the articles were published in the 2000’s, followed by the 1990’s, 1980’s, 1970’s and 1960’s, respectively. All of the articles were published in five journals. There were 50 studies at level II, 28 at level V, 10 at level IV, 7 at level III, and 5 at Level I.

Conclusion: This systematic review provides an overview of the most cited articles, published in general medical journals. The number of citations provides an indication of the quality of evidence. However, researchers and clinicians should use standardized assessment tools rather than solely rely on the number of citations in order to judge the quality of published articles.

Keywords: Most-cited articles, Bibliometrics, Level of evidence, Citation classics, General medical journals, Article quality.

(Please cite as: Ahmad SJS, Ahmed AR, Kowalewski KF, Nickel F, Rostami K, Stocker CJ, et al. Citation classics in general medical journals: assessing the quality of evidence; a systematic review. Gastroenterol Hepatol Bed Bench 2020;13(2): 101-114).

Primary sclerosing cholangitis is a chronic cholestatic liver disease defined by strictures of the biliary tree which could ultimately lead to liver cirrhosis and cholangiocarcinoma. Although the exact underlying etiology of this disorder is not fully understood, the pathology is believed to be caused by immune mediated mechanisms. Growing body of evidence suggests several treatment modalities mainly focusing on the inflammation aspect of this disorder. However, there is still no consensus regarding the best treatment option for these patients. Thus, the present study aimed to review the current treatment options for patients with primary sclerosing cholangitis.

Keywords: Inflammatory bowel disease, Primary sclerosing cholangitis (PSC), Management, Vancomycin, Cholestasis, Cholangitis.

(Please cite as: Iravani SH, Dooghaie-Moghadam A, Razavi-Khorasani N, Moazzami B, Dowlati Beirami AR, Mansour-Ghanaei AR, et al. An update on treatment options for primary sclerosing cholangitis. Gastroenterol Hepatol Bed Bench 2020;13(2):115-124).

Aim: This study aimed to estimate the cure proportion and effects of related factors on colorectal cancer in Iranian patients after surgery.

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer death. The relative survival of CRC varies worldwide given the quality of care, including surgical techniques.

Methods: This retrospective cohort study was conducted on 490 patients, aged 20–94 years, with colorectal cancer. All the colorectal cancer patients undergoing surgery in Faghihi hospital, Shiraz University of Medical Sciences were prospectively followed-up for 8 years from 2008 to March 8, 2016. We used parametric cure model (mixture and non-mixture) to estimate the cure proportion and the adjusted hazard ration (HR) for colorectal cancer mortality after surgery. Data were analyzed by the “flexsurvcure” package in R software (version 3.4.2).

Results: The median age of patients was 57.5 (interquartile range =18) years. Specifically, 56.33% of the patients were male. The median time of follow-up in patients was 618 days. The cumulative survival proportion varied from 0.90 to 0.49 which indicated a reduction followed by a flat line in the probability of survival by sex. The flexible survival for adjusted cure proportion (%) was 68.3. Only obesity was associated with a decreased risk of mortality (HR=0.34; 95% CI: 0.12-0.97).

Conclusion: The overall eight-year survival proportion and adjusted cure proportion for CRC were 49% and 68.3%, respectively. Knowing the cure proportion and its related factors in patients with CRC, better services can be provided. Thus, early detection and screening strategies are required to reduce mortality and increase survival of patients.

Keywords: Cure proportion, Related factors, Colorectal cancer, Parametric cure model.

(Please cite as: Izadi N, Koohi F, Safarpour M, Naseri P, Rahimi S, Khodakarim S. Estimating the cure proportion of colorectal cancer and related factors after surgery in patients using parametric cure models. Gastroenterol Hepatol Bed Bench 2020;13(2):125-132).

            Aim: This study aims to determine oxidant status and left ventricular mass index (LVMI) and their relationship with mild hyperbilirubinemia in patients with Gilbert syndrome (GS).

Materials and Methods: A total of 84 patients, including 41 (48.8%) patients with GS and 43 (51.2%) patients without GS, were included in the study. Total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were studied for oxidant status.

Results: TAS was found to be higher in the GS patients compared to the non-GS patients (1.7±0.1 vs. 1.5±0.2; p=0.002); there was no significant difference between the groups in terms of mean TOS and mean OSI (p>0.05). No significant difference was observed between the GS and non-GS patients in terms of mean left ventricular volume and mean LVMI (p>0.05). However, subgroup analysis based on sex showed that GS patients had lower LVMI for both sexes. In GS patients, TAS level had a positive correlation with albumin (r=0.319; p=0.042), triglyceride (r=0.392; p=0.011), total bilirubin (r=0.420; p=0.006), direct bilirubin (r=0.361; p=0.020), and indirect bilirubin (r=0.338; p=0.0311) levels; no correlation was revealed between TAS level and other laboratory findings (p>0.05). The regression model showed that risk factors of direct bilirubin (?±SE=0.13±0.03; p<0.001), uric acid (?±SE=0.04±0.01; p=0.001), and albumin (?±SE=0.17±0.04; p<0.001) were independent predictors of TAS level.

Conclusion: This study revealed a relationship between mild hyperbilirubinemia and antioxidant balance in GS. Although statistical significance was not reached, LVMI was found to be lower in the GS group compared to the non-GS group for both sexes.

Aim: we aimed to determine the virological response and safety of Sofosbuvir-based direct-acting antiviral agents (DAAs) in chronic hepatitis C (CHC) patients on long-term hemodialysis (HD).

Background: With the advent of interferon-free DAAs, the treatment of CHC has been revolutionized. Pakistan is among the countries where novel sofosbuvir (SOF)-free antiviral agents are not available.

Methods: This non-randomized, single-arm, open-label study enrolled all HD patients with chronic HCV infection after informed consent. They were treated with SOF in combination with Ribavirin (RBV) with either interferon (IFN group) or daclatasvir (DAC group), with the virological response assessed according to standard guidelines. Data were analyzed using SPSS version 20.00.

Results: Out of 133 patients, the majority (72.9%) were males with the mean age of 31.92 ± 9.88 years. Most patients (50.3%) had HCV genotype (GN) 1, followed by GN 3 in 42.9%, 4 in 1.48% and 2 in 0.7%, while mix GN was documented in 6 (4.4%) patients. Among these, 60 (45.1 %) patients received standard SOF, IFN, and RBV (IFN group) and 73 (54.9 %) received SOF, DAC and RBV (DAC group). End of treatment and sustained virological response at 12 weeks post-treatment were achieved in 133 (100%) and 129 (97 %) patients, respectively. The adverse effects were anemia in 58 (43.6 %) patients and elevated alanine transaminases in 11 (8.1%) patients.

Conclusion: SOF in combination with either IFN or DAC is an equally efficacious and effective treatment regimen for patients on maintenance HD, especially in resource-poor countries.

Keywords: End-stage renal disease, hemodialysis, Hepatitis C virus, Interferon, Sofosbuvir, Sustained virological response.

(Please cite as: Mandhwani R, Hanif FM, Lail GH,  Luck NH, Khalid MA, Muh ul Haque MM, et al. Use of Sofosbuvir based regimen in patients with end-stage renal disease and chronic hepatitis C; an open label, non-randomized, single arm, single center study from Pakistan. Gastroenterol Hepatol Bed Bench 2020;13(2):141-146).

Aim: This study aimed to investigate whether plasma miR-21 and miR-92a levels may be used to differentiate between patients with irritable bowel syndrome (IBS), ulcerative colitis (UC), and colorectal cancer (CRC).

Background: miRNA expression profiles are well characterized in CRC, but these expression profiles in UC and IBS remain promising. Screening of high-risk individuals for these diseases has substantial clinical benefits.

Methods: This was a case-control study. We quantified plasma miR-21 and miR-92a expression levels in 100 samples (37 with active UC, 33 with CRC, and 30 with IBS as well as 30 healthy controls) using real-time PCR. Their diagnostic performance for discriminating these diseases was assessed using receiver-operation characteristic curve (AUC-ROC).

Results: The studied miRNAs were differentially expressed among all participated groups. Plasma miR-21 and miR-92a levels exhibited significant upregulation in CRC as compared to IBS, UC, and healthy subjects. Both miRNAs were upregulated in the UC group as compared to IBS and healthy subjects. ROC analysis revealed promising diagnostic performance for miR-21 and miR-92a in discriminating UC from non-UC groups (IBS and healthy subjects) with AUCs of 0.844 and 0.979 respectively. It also distinguished between CRC and UC with AUCs of 0.968 and 0.887 respectively and with reasonable sensitivities and specificities.

Conclusion: Circulating miR-21 and miR-92a can be exploited not only as potential noninvasive biomarkers for detection of CRC, but also for differentiation between functional and organic colorectal disorders.

Keywords: miR-21, miR-92a, Colorectal cancer, Irritable bowel syndrome, Ulcerative colitis.

(Please cite as: Ahmed Hassan E, El-Din Abd El-Rehim AS, Mohammed Kholef EF, Abd-Elgwad Elsewify W. Potential role of plasma miR-21 and miR-92a in distinguishing between irritable bowel syndrome, ulcerative colitis, and colorectal cancer. Gastroenterol Hepatol Bed Bench 2020;13(2):147-154).

Aim: To assess the immunological reactions and gene expression level in the celiac disease (CD) patients under a gluten-free diet (GFD).

Background: CD is an autoimmune disorder in genetic susceptible individuals and lifelong gluten free diet is the effective treatment method. It seems that treated patients will experience a normal life style though there are documents about some potential damages.

Methods: Gene expression profiles of treated CD patients and healthy samples were obtained from Gene Expression Omnibus (GEO) and compared to find the differentially expressed genes (DEGs). The identified DEGs were introduced in the network and gene ontology (GO) analysis.

Results: Ten differentially expressed genes (DEGs) including CCR2, IRF4, FASLG, CCR4, ICOS, TNFSF18, BACH2, LTF, PRM1, and PRM2 were investigated via network analysis. Seven clusters of biological processes (BP) were determined as the affected BP. PThe finding led to introduction of CCR2, IRF4, FASLG, CCR4, and ICOS as the potential immunological markers that are still active despite GFD in the treated CD patients.

Conclusion: The results of this study indicated that the immune system is already active in treated CD patients despite GFD treatment and exposure to gluten causes potential immunological reactions in these patients.

Keywords: Celiac disease, Gene expression, Network analysis, Immune system.

(Please cite as: Rostami-Nejad M, Razzaghi Z, Esmaeili S, Rezaei-Tavirani S, Akbarzadeh Baghban AR, Vafaee R. Immunological reactions by T cell and regulation of crucial genes in treated celiac disease patients. Gastroenterol Hepatol Bed Bench 2020;13(2):155-160).

Aim: To understand the molecular difference between H.pylori negative and positive gastric cancer, a regulatory network analysis is investigated.

Background: Helicobacter pylori as the one of the most leading causes of gastric cancer is yet to be studied in terms of its molecular pathogenicity.

Methods: Cytoscape version of 3.7.2 with its applications was employed to conduct this study via corresponding algorithms.

Results: A total of 161 microRNAs were identified differentially expressed in the comparison of two groups of gastric cancer including negative and positive with H.pylori infection. CluePedia explored the regulatory network and found down-regulation dominant while considering the linked hub genes.

Conclusion: It can be concluded that the presented microRNAs and target genes could have associations with H.pylori carcinogenesis in gastric cancer through dysregulation of some vital biological processes. These microRNAs and target genes include hsa-miR-943, hsa-miR-935, hsa-miR-367, hsa-miR-363, hsa-miR-25, and hsa-miR-196b and ADRA1A, KCNA4, SOD1, and SESN3, respectively. However, verification analysis in this regard is required to establish these relationships.

Keywords: Helicobacter pylori, Gastric cancer, MicroRNA, Regulatory network, Hub.

(Please cite as: Abdi S, Zamanian Azodi M, Rezaei-Tavirani M, Razzaghi MR, Heidari MH, Akbarzadeh Baghban AR. Differentiation of H. pylori-negative and positive gastric cancer via regulatory network analysis. Gastroenterol Hepatol Bed Bench 2020;13(2):161-167).

Aim: This research studied the effects of glycyrrhizic acid (GA) on apoptosis induced with by titanium dioxide (NTiO2) in the liver of rats.

Background: It is widely accepted that the contamination resulting from nanoparticles (NPs) is an emerging dangerous issue. Metal oxide nanoparticles have high environmental stability and cause toxicity in the food chain. Thus, the present study investigated the anti-apoptotic effects of glycyrrhizic acid (GA) on the hepatotoxicity generated by titanium dioxide (NTiO2) NPs in the liver tissue.

Methods: Thirty-two male Wistar rats were randomly divided into four groups. NTiO2-treated rats were given 300 mg / kg of NTiO2 solution via gavage for 14 days; GA-treated were administered 100 mg/kg GA for 14 days; protection group was pre-treated with GA before NTiO2 administration for 7 days. Then, apoptotic index was evaluated through immunolocalization of Bax and Bcl-2 and TUNEL assay.

Results: we found that HSCORE of Bax expression and apoptotic index experienced a significant increase with NTiO2 (P <0.001), while Bcl-2 expression significantly diminished in NTiO2-treated rats (P <0.001). The results revealed that the increased Bax expression and apoptotic index were reversed by GA and enhanced the activities of Bcl2.

Conclusion: The results revealed that GA effectively attenuated apoptosis against NTiO2 in rats.

Keywords: NTiO2, Immunohistochemistry, TUNEL, Apoptosis, Histopathological.

(Please cite as: Orazizadeh M, Khorsandi LS, Mansouri E, Fakhredini FS. The effect of glycyrrhizin acid on Bax and Bcl2 expression in hepatotoxicity induced by Titanium dioxide nanoparticles in rats. Gastroenterol Hepatol Bed Bench 2020;13(2):168-176).

Aim: To estimate the number of confirmed cases and the rate of death and also to investigate the cause of death in Italy, Iran and South Korea in the next month.

Background: Growing number of confirmed and deaths cases from the coronavirus worldwide, particularly in Italy, Iran and South Korea, has resulted concerns about the future of these countries and their deterioration. Also the European region is likely to face more casualties due to the delay in the virus reaching most of its regions and, of course, as the trend continues.

Methods: We conducted a simulation in both current and ideal situation for the next month to predict the death rate and examine the reason for the difference in Italy, Iran and South Korea individually. If we assume the cultural and political factors and age pyramids distribution are similar across regions, the differences are mainly due either to the heavier health-care burden owing to the larger population or to the medical facilities diversities.

Results: Our results for Italy showed higher death number, but the rate would be more for Iran. South Korea is also expected to have a smaller increase in the number of confirmed cases and deaths compared to Iran and Italy by the next month.

Conclusion: Given the prevailing conditions around the world and the increasing number of casualties, it is essential that all countries, especially those with fewer days of involvement, shall do their best to avoid major losses and damages.

Keywords: COVID-19, Coronavirus, Mortality, Iran, Italy, South Korea.

(Please cite as: Shojaee S, Pourhoseingholi MA, Ashtari S, Vahedian-Azimi A, Asadzadeh-Aghdaei H, Zali MR. Predicting the mortality due to Covid-19 by the next month for Italy, Iran and South Korea; a simulation study. Gastroenterol Hepatol Bed Bench 2020;13(2):177-179).

Rujittika Mungmunpuntipantip¹, Viroj Wiwanitkit²

¹26 Medical Center, Bangkok Thailand

²Honorary professor, Dr DY Patil University, Pune, India; visiting professor, Hainan Medical University, Haikou, China

Type 1 myotonic dystrophy (MD) is a rare inherited disease which presents with skeletal muscle weakness and myotonia. Involvement of smooth muscles is also common and mainly manifests in the gastrointestinal tract. We report a case of type 1 MD who presented with dysphagia and was found to have unique esophageal manometry findings. A 57-year-old male patient presented with dysphagia for the last few months. Past medical history was significant for type 1 myotonic muscular dystrophy, gastroesophageal reflux disease, diaphragmatic paralysis, and obstructive sleep apnea. Both his father and brother died in their 50s because of unclear respiratory problems. He was a former smoker and did not drink alcohol. Review of systems was unremarkable. His neurological examination was significant for bilateral facial muscle weakness and mild ptosis. He had atrophy and weakness of the distal upper and lower extremities. Deep tendon reflexes were absent. Upper endoscopy and 24-hour esophageal pH testing were non-diagnostic. Finally, esophageal manometry revealed elevated lower esophageal sphincter (LES) pressure, elevated upper esophageal sphincter (UES) pressure, and very week peristalsis of the esophageal body. Esophageal involvement is common in type 1 MD manifesting with dysfunction of UES, esophageal body, and LES. Manometry usually describes a reduced resting tone of the UES and LES. The patient had elevated LES pressure and week peristalsis of the esophageal body consistent with achalasia. He also had an elevated UES pressure consistent with cricopharyngeal achalasia. This is the opposite of what is expected in type 1 MD.

Keywords: Esophageal achalasia, Dysphagia, Myotonic dystrophy.

(Please cite as: Ghazaleh S, Nehme CH, Khader Y, Hasan S, Nawras A. Combined achalasia and cricopharyngeal achalasia in a patient with type 1 myotonic dystrophy: a case report. Gastroenterol Hepatol Bed Bench 2020;13(2):181-183).

The most common sites of metastasis for esophageal cancers include the liver, lungs, and bones. We report a rare case of esophageal adenocarcinoma with metastasis to the subcutaneous perianal region as well as to the small bowel. Physicians should consider the possibility of metastasis in a patient with esophageal adenocarcinoma even after the onset of remission. It is essential to examine these patients and maintain a high index of suspicion for possible metastases. Early recognition helps in the accurate staging of the disease and enables the initiation of life-prolonging therapy and achieving meaningful palliation.

Keywords: Unusual sites, Metastases, Esophageal adenocarcinoma.

(Please cite as: Amini A, Koury E, Vaezi Z, Leathersich A, Zafar S, Chahla E. Two unusual sites of metastases of esophageal adenocarcinoma. Gastroenterol Hepatol Bed Bench 2020;13(2):184-187).

Pyodermatitis-pyostomatitis vegetans (PD-PSV) is a very rare inflammatory disease characterized by exudative pustular lesions of the skin and mucous membranes. The pathogenesis is unknown, but it may be related to immune or infectious processes. It is usually associated with inflammatory bowel disease (IBD). We describe a 32-year-old male with PD-PSV associated with manifestations suggestive of autoimmune hepatitis (AIH). To the best of our knowledge, this association has not been reported previously.

Keywords: Pyoderma vegetans, Pyostomatis, Autoimmune hepatitis, Case report.

(Please cite as: Tharwat S, Eltoraby EE. Pyodermatitis-pyostomatitis vegetans associated with autoimmune hepatitis: unreported co-existence. Gastroenterol Hepatol Bed Bench 2020;13(2):188-190).