Tsai-Yuan Hsieh

Molecular pathogenesis of Gilbert's syndrome: decreased Tata-binding protein binding affinity of ugt1a1 gene promoter

Objectives Gilberts syndrome is a congenital, nonhemolytic, unconjugated hyperbilirubinemia. The most common genotype of Gilberts syndrome is the homozygous polymorphism, A(TA)7TAA, in the promoter of the gene for UDP-glucuronosyltransferase 1A1 (UGT1A1), with a thymine adenine insertion in the TATA-box-like sequence, which results in a decrease in UGT1A1 activity. The mechanism responsible for this decrease in UGT1A1 activity, however, has not been elucidated. To clarify the mechanism underlying this deficiency in UGT1A1 activity in patients with Gilberts syndrome. Methods The promoter activity assay using the wild-type A(TA)6TAA or the mutant A(TA)7TAA promoter and a luciferase reporter was performed in two different hepatoma cell lines. The binding affinity for a nuclear protein complex or for TATA-binding protein was evaluated by a competitive electophoretic mobility shift assay using wild-type or mutant TATA-box-like oligonucleotide probes and nuclear extract or TATA-binding protein. The formation of complexes between TATA-binding protein and wild-type or mutant oligonucleotide probes was also studied by a quantitive electophoretic mobility shift assay. Results A TA insertion in the TATA-box-like sequence of the promoter activity of UGT1A1 gene. A competitive electrophoretic mobility shift assay showed a decrease in nuclear proteincomplex binding affinity and TATA-binding protein binding affinity of the mutant TATA-box-like sequence A(TA)7TAA. When the mutants A(TA)5TAA and A(TA)8TAA were also compared, quantitative electrophoretic mobility shift assay demonstrated that the TATA-binding protein binding affinity progressively decreased as the number of TA repeats in the TATA-box-like sequence increased. Conclusion TA insertion in the TATA-box-like sequence of the UGT1A1 promoter affected its binding affinity for TATA-binding protein, causing a decrease in its activity. This explains the pathogenesis of Gilberts syndrome.

Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases

In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases.

Endoscopic submucosal dissection with the pulley method for early-stage gastric cancer (with video)

BACKGROUND Using EMR techniques, physicians frequently remove tumors >15 mm by piecemeal resection, which is associated with an increased rate of disease recurrence and difficulty in histologically evaluating the specimen. Endoscopic submucosal dissection (ESD) of early-stage gastric cancer improves the rate of successful en bloc resection, but it is associated with more complications, such as bleeding and perforation, than conventional EMR. OBJECTIVE To describe a simple technique that uses the pulley method to facilitate ESD procedures in the excision of large early-stage gastric cancers. DESIGN Case series. SETTING Tertiary medical center in Taiwan. PATIENTS AND METHODS Eleven patients with early-stage gastric cancers or adenomas >20 mm underwent ESD. INTERVENTIONS The pulley method with standard clips and dental floss was used to provide traction to improve visualization of the dissection plane during ESD. MAIN OUTCOME MEASUREMENT Proportion with complete en bloc resection. RESULTS En bloc resection of the lesion was achieved in 11 patients. No perforation or emergent surgery was noted. LIMITATIONS One endoscopist performed all procedures, and only 11 patients were studied in an uncontrolled manner. CONCLUSIONS The pulley method seems to facilitate en bloc ESD of early-stage gastric cancers >20 mm.

A prospective trial of variable stiffness colonoscopes with different tip diameters in unsedated patients

OBJECTIVES:Few data exist comparing the clinical versatility of variable stiffness (VS) colonoscopes with different tip diameters and stiffness ranges. We compared the intubation time and success rate, maneuvering ease, and patient comfort of three colonoscopes: pediatric VS (PVSC), nonmagnifying adult VS (AVSC), and magnifying VS (MVSC).METHODS:Two hundred sixteen consecutive patients scheduled for routine colonoscopy were randomized to undergo colonoscopy with one of the three different colonoscopes (PVSC N = 72, AVSC N = 72, MVSC N = 72). Outcome measurements included time required for cecal intubation, success rate for cecal intubation, maneuvering ease, and patient comfort.RESULTS:The overall success rate for cecal intubation was 95.83%. Intubation time was significantly different among the groups (PVSC 12.88 ± 7.11 min, AVSC 9.25 ± 5.16 min, MVSC 9.62 ± 5.55 min; P < 0.01). Intubation time with PVSC required about 3 min more when compared with AVSC or MVSC. Multivariate analyses revealed that colonoscopy with AVSC required 3 min less when compared with PVSC (P= 0.03). Age greater than 55 yr, waist circumference, prior hysterectomy, and pain experienced by patients were also factors affecting intubation time.CONCLUSIONS:In this study, a PVSC might not decrease patient discomfort or intubation time. The ideal colonoscope is the AVSC that has a modest diameter and stiffness range and thus is capable of achieving both a short intubation time and an acceptable comfort level. We also should bear in mind that MVSC has an additional function of magnifying observation.

Endoscopic Submucosal Dissection for Early Colorectal Neoplasms: Clinical Experience in a Tertiary Medical Center in Taiwan

Objectives. Endoscopic submucosal dissection (ESD) is a promising technique to treat early colorectal neoplasms by facilitating en bloc resection without size limitations. Although ESD for early gastrointestinal epithelial neoplasms has been popular in Japan, clinical experience with colorectal ESD has been rarely reported in Taiwan. Methods. From March 2006 to December 2011, 92 consecutive patients with early colorectal neoplasms resected by ESD at Tri-Service General Hospital were included. ESD was performed for colorectal epithelial neoplasms with a noninvasive pit pattern which had the following criteria: (1) lesions difficult to remove en bloc with a snare, such as laterally spreading tumors-nongranular type (LST-NG) ≧20 mm and laterally spreading tumors-granular type (LST-G) ≧30 mm; (2) lesions with fibrosis or which had recurred after endoscopic mucosal resection with a nonlifting sign. Results. The mean age of the patients was 66.3 ± 12.9 years, and the male-female ratio was 1.8 : 1. The mean tumor size was 37.2 ± 17.9 mm. The en bloc resection rate was 90.2% and the R0 resection rate was 89.1%. Perforations during ESD occurred in 11 patients (12.0%) and all of them were effectively treated by endoscopic closure with hemoclips. No delayed perforation or postoperative bleeding was recorded. There were no procedure-related morbidities or mortalities. Conclusion. ESD is an effective method for en bloc resection of large early colorectal neoplasms and those with a nonlifting sign. An endoscopic technique to close perforations is essential for colorectal ESD.

Isolated gastric variceal bleeding caused by splenic lymphoma-associated splenic vein occlusion

Isolated gastric varices (IGV) can occur in patients with left-sided portal hypertension resulting from splenic vein occlusion caused by thrombosis or stenosis. In left-sided portal hypertension, blood flows retrogradely through the short and posterior gastric veins and the gastroepiploic veins, leading to the formation of an IGV. The most common causes of splenic vein occlusion are pancreatic diseases, such as pancreatic cancer, pancreatitis, or a pseudocyst. However, various other cancers, such as colon, gastric, or renal cancers, have also been known to cause splenic vein occlusion. Our patient presented with a rare case of IGV bleeding induced by splenic lymphoma-associated splenic vein occlusion. Splenectomy, splenic artery embolization, and stenting of the splenic vein are the current treatment choices. Chemotherapy, however, is an alternative effective treatment for splenic vein occlusion caused by chemotherapy-sensitive tumors. Our patient responded well to chemotherapy with a cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone regimen, and the splenic vein occlusion resolved after the lymphoma regressed.

Roux-en-Y reconstruction does not require gastric decompression after radical distal gastrectomy.

AIM To determine whether routine nasogastric (NG) decompression benefitted patients undergoing radical gastric surgery. METHODS Between January 1998 and December 2008, 519 patients who underwent distal gastrectomy for gastric cancer were retrospectively divided into 2 time-period cohorts; those treated with Billroth II (BII) reconstruction in the first 6 years and those with Roux-en-Y (RY) reconstruction in the last 5 years. In the latter group, the patients were further divided into 2 subgroups; with and without nasogastric decompression. RESULTS Postoperatively, there were no significant differences in the number of anastomotic leaks between the 3 groups. In the tubeless RY group, time to semi-liquid diet was significantly shorter than in the other 2 groups (4.4 d ± 1.4 d vs 7.2 d ± 1.3 d and 5.9 d ± 1.2 d, P = 0.005). The length of postoperative stay was significantly increased in patients with BII reconstruction compared with patients with RY reconstruction with/without NG decompression (15.4 d ± 4.3 d in BIIgroup vs 12.6 d ± 3.1 d in decompressed RY and 11.4 d ± 3.4 d in the tubeless RY group, P = 0.035). The postoperative pneumonia rate was lowest in the tubeless group and highest in the BII group (1.4% vs 4.6%, P = 0.01). Severe sore throat was noted in 59 (20.7%) members of the BII group, 18 (17.4%) members of the decompressed RY group and 6 (4.2%) members of the tubeless RY group. Fewer patients in the tubeless group complained of severe sore throat (P = 0.001). CONCLUSION This study provides support for abandoning routine NG decompression in patients undergoing subtotal gastrectomy with Roux-en-Y gastrojejunostomy.

Clinical characteristics of early onset pancreatic adenocarcinoma: a medical center experience and review of the literature.

To the Editor: Pancreatic adenocarcinoma (PAC) develops mostly in older individuals and is unusual in patients younger than 30 years and rare before the age of 50 years. The clinical features of young patients with PAC in the Western regions have been reported; however, this has not been the case in Asia. The objective of this study was to describe the clinicopathological features and longterm outcomes of young Chinese PAC patients.

Outcome and Safety of Anterograde and Retrograde Single-Balloon Enteroscopy: Clinical Experience at a Tertiary Medical Center in Taiwan.

Single-balloon enteroscopy (SBE) is designed for identifying possible small bowel lesions with balloon-assisted enteroscopy that allows deep intubation of the intestine. However, data regarding the outcome and safety of SBE remain limited. We conducted this study to evaluate the outcome and safety of anterograde and retrograde SBE approaches. This retrospective review from a tertiary medical center in Taiwan included endoscopic reports and chart data from 128 patients with 200 anterograde and retrograde procedures from September 2009 to November 2014. In this study, the most common indication for both anterograde and retrograde SBE was obscure gastrointestinal bleeding (64.4% vs. 60.6%). There were no significant differences between anterograde and retrograde approaches in terms of the diagnostic yield (69.3% vs. 52.5%) and intervention rate (23.8% vs. 17.2%). The procedure time was shorter for anterograde SBE than for retrograde SBE (68.1 ± 23.9 vs. 76.8 ± 27.7 min, P = 0.018). In addition, among the subgroup of patients with obscure gastrointestinal bleeding, the most common etiologies for those in different age-groups were angiodysplasia (≥ 65 years), non-specific ulcers (30–64 years), and Meckel’s diverticulum (< 30 years). The major complication rate during the study was 1.5%; the rate of asymptomatic hyperamylasemia was higher for patients who underwent anterograde SBE than for those who underwent retrograde SBE (13.9% vs. 2%, P = 0.005). The outcome and safety of anterograde and retrograde SBE are similar. However, anterograde SBE has a shorter procedural time and a higher rate of asymptomatic hyperamylasemia.

Hepatocellular carcinoma with colonic metastasis.

Hepatocellular carcinoma with colonic metastasis is rare. It mainly occurs by direct invasion and presents with bloody stools. We describe a patient with haematogenous metastasis to the rectum who presented with tenesmus. To our knowledge, such an association has not been reported previously. Colonic metastasis should be considered when patients with hepatocellular carcinoma present with bloody stools or tenesmus.