Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis

Chronic pancreatitis is known to be a heterogeneous disease with varied etiologies.Tropical calcific pancreatitis(TCP) is a severe form of chronic pancreatitis unique to developing countries.With growing evidence of genetic factors contributing to the pathogenesis of TCP,this review is aimed at compiling the available information in this field.We also propose a two hit model to explain the sequence of events in the pathogenesis of TCP.

Effect of Chaiqinchengqi decoction on sarco/endoplasmic reticulum Ca^(2+)-ATPase mRNA expression of pancreatic tissues in acute pancreatitis rats

AIM: To investigate the effect of Chaiqinchengqi decoction (CQCQD) on sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) mRNA expression of pancreatic tissues in acute pancreatitis (AP) rats. METHODS: Thirty Sprague-Dawley (SD) rats were randomized into control group, AP group and CQCQD group (n = 3 × 10). The rats in the CQCQD group were intragastrically administered with CQCQD (10 mL/kg every 2 h) after induction of AP by intraperitoneal injection of caerulein (50 μg/kg.h × 5) within 4 h. At 6 h after the induction of AP model, pancreatic tissues were collected for the pathological observation, mRNA extraction for determination of SERCA1 and SERCA2 mRNA expression or pancreatic acinar cell isolation for measurement of fluorescence intensity (FI) of intracellular calcium ion concentration [Ca2+]i. RESULTS: There was no expression of pancreatic SERCA1 mRNA in the control group and the AP group. The expression of pancreatic SERCA2 mRNA in the AP group was down-regulated (expression ratio = 0.536; P = 0.001) compared with the control group, while that in the CQCQD group was up-regulated (expression ratio= 2.00; P = 0.012) compared with AP group. The FI of intracellular [Ca2+] of pancreatic acinar cells in the AP group (138.2 ± 23.1) was higher than the C group (111.0 ± 18.4) and the CQCQD group (118.7 ± 15.2 ) (P < 0.05) and the pancreatic pathological score in the CQCQD group was lower than that in the AP group (5.7 ± 1.9 vs 9.2 ± 2.7, P < 0.05).CONCLUSION: CQCQD can up-regulate the expression of SERCA2 mRNA of pancreatic tissues, reduce intracellular calcium overload and relieve pancreatic tissue lesions.

Intraductal papillary mucinous neoplasm in chronic calcifying pancreatitis:Egg or hen?

Intraductal papillary mucinous neoplasm(IPMN)is an increasingly reported entity.Extensive pancreatic calcification is generally thought to be a sign of chronic pancreatitis,but it may occur simultaneously with IPMN leading to diagnostic difficulties.We report a case of a patient initially diagnosed with chronic calcifying pancreatitis who was later shown to have a malignant IPMN.This case illustrates potential pitfalls in the diagnosis of IPMN in the case of extensive pancreatic calcification as well as clues that may lead the clinician to suspecting the diagnosis.The possible mechanisms of the relation between pancreatic calcification and IPMN are also reviewed.

Unicentric Castleman's disease of the pancreas with massive central calcification

Unicentric Castleman＇s disease of the pancreas is extremely rare, with only six cases described in the worldwide literature. An asymptomatic case of unicentric, hyaline, vascular-type Castleman＇s disease （UCD） localized to the tail of bhe pancreas with central calcification imitating a primary neoplasm of the pancreas is presented. This is the first description of endosonographic and endoscopic retrograde pancreatographic findings of pancreatic UCD. Additionally, computed tomography, histological and serologic findings are reported.

Comprehensive screening for reg1α gene rules out association with tropical calcific pancreatitis

AIM: To investigate the allelic and haplotypic association of reg1α gene with tropical calcific pancreatitis (TCP). Since TCP is known to have a variable genetic basis, we investigated the interaction between mutations in the susceptibility genes, SPINK1 and CTSB with reg1α polymorphisms. METHODS: We analyzed the polymorphisms in the reg1α gene by sequencing the gene including its promoter region in 195 TCP patients and 150 ethnically matched controls, compared their allele and haplotype frequencies, and their association with the pathogenesis and pancreaticolithiasis in TCP and fibro-calculous pancreatic diabetes. RESULTS: We found 8 reported and 2 novel polymo-rphisms including an insertion-deletion polymorphism in the promoter region of reg1α. None of the 5' UTR variants altered any known transcription factor binding sites, neither did any show a statistically significant association with TCP. No association with any reg1α variants was observed on dichotomization of patients based on their N34S SPINK1 or L26V CTSB status. CONCLUSION: Polymorphisms in reg1α gene, including the regulatory variants singly or in combination with the known mutations in SPINK1 and/or CTSB genes, are not associated with tropical calcific pancreatitis.

Characteristics and mechanism of enzyme secretion and increase in [ Ca^(2+)]_i in Saikosaponin.(I)stimulated rat pancreatic acinar cells

AIM: This investigation was to reveal the characteristics and mechanism of enzyme secretion and increase in [Ca2+]i stimulated by saikosaponin(I) (SA(I)) in rat pancreatic acini. METHODS:Pancreatic acini were prepared from male Wistar rats. Isolated acinar cells were suspended in Eagle's MEM solution. After adding drugs, the incubation was performed at 37 degrees for a set period of time. Amylase of supernatant was assayed using starch-iodide reaction. Isolated acinar single cell was incubated with Fura-2/AM at 37 degrees, then cells were washed and resuspended in fresh solution and attached to the chamber. Cytoplasm [Ca2+]i of a single cell was expressed by fluorescence ratio F340/F380 recorded in a Nikon PI Ca2+ measurement system. RESULTS: Rate course of amylase secretion stimulated by SA(I) in rat pancreatic acini appeared in bell-like shape. The peak amplitude increased depended on SA(I) concentration. The maximum rate responded to 1 x 10(-5)mol/L SA(I) was 13.1-fold of basal and the rate decreased to basal level at 30 min. CCK-8 receptor antagonist Bt(2)-cGMP markedly inhibited amylase secretion stimulated by SA(I) and the dose-effect relationship was similar to that by CCK-8. [Ca2+]i in a single acinar cell rose to the peak at 5 min after adding 5 x 10(-6)mol/L SA(I) and was 5.1-fold of basal level. In addition, there was a secondary increase after the initial peak. GDP could inhibit both the rate of amylase secretion and rising of [Ca2+]i stimulated by SA(I) in a single pancreatic acinar cell. CONCLUSION: SA(I) is highly efficient in promoting the secretion of enzymes synthesized in rat pancreatic acini and raising intracellular [Ca2+]i. Signaling transduction pathway of SA(I) involves activating special membrane receptor and increase in cytoplasm [Ca2+]i sequentially.

E-cadherin and β-catenin expression in pancreatic intraepithelial neoplasia and pancreatic adenocarcinoma

Objective: To investigate the significance of abnormal E-cadherin and β-catenin expression in pancreatic intraepithelial neoplasia (PanIN) and pancreatic adenocarcinoma. Methods:Pancreatic samples of 156 cases were retrospectively studied from surgery and autopsy in Changhai hospital from January 2001 to December 2003, from which tissue microarray blocks containing 129 PanIN-1A lesions, 104 PanIN-1B lesions, 22 PanIN-2 lesions, 11 PanIN-3 lesions, and 121 pancreatic ductal adenocarcinomas and corresponding paracancerous tissues were constructed. EnVision method of immunohistochemistry was used to detect the E-cadherin and β-catenin expression. The correlation between the abnormal E-cadherin and β-catenin expression and clinicopathological parameters was analysed. Results: The rate of E-cadherin abnormal expression was significant in ductal adenocarcinomas compared with the PanIN lesions and normal ducts(64.5%,32.3%,0%), moreover, the rate of E-cadherin abnormal expression was in relation to differentiation, lymph node metastasis and perineural invasion of pancreatic adenocarcinoma(P<0.05). There was remarkable increase in the E-cadherin cytoplasmic expression in PanIN lesions and ductal adenocarcinomas compared with normal ducts. The rate of β-catenin abnormal expression was found to be related with lymph node metastasis and perineural invasion of pancreatic adenocarcinoma(P<0.05). The expression of β-catenin cytoplasm and/or nucleus was significant in high-grade PanIN lesions and ductal adenocarcinomas compared with low grade PanIN lesions or normal ducts(P<0.05). There was a positive relationship between the E-cadherin and β-catenin expression in PanIN lesions and ductal adenocarcinomas (P<0.01, P<0.05). Conclusion: There is aberration in the expression of the E-cadherin and β-catenin in PanIN lesions and ductal adenocarcinomas, suggesting the E-cadherin and β-catenin changes is not only related with the biological action and prognosis, but also involved in pancreatic carcinogenesis.

Comparative identification of Ca～(2+) channel expression in INS-1 and rat pancreatic β cells

AIM： To identify and compare the profile of Ca^2＋ channel subunit expression in INS-1 and rat pancreatic β cells.METHODS： The rat insulin-secreting INS-1 cell line was cultured in RPMI-1640 with Wistar rats employed as islet donors. Ca^2＋ channel subunit expression in INS-1 and isolated rat β cells were examined by reverse transcription polymerase chain reaction （RT-PCR）. Absolute real-time quantitative PCR was performed in a Bio-Rad iQ5 Gradient Real Time PCR system and the data analyzed using an iQ5 system to identify the expression level of the Ca^2＋ channel subunits. RESULTS： In INS-1 cells, the L-type Ca^2＋ channel 1C subunit had the highest expression level and the TPRM2 subunit had the second highest expression. In rat β cells, the TPRC4β subunit expression was dominant and the expression of the L-type lC subunit exceeded the 1D subunit expression about two-fold. This result agreed with other studies, confirming the important role of the L-type lC subunit in insulinsecreting cells, and suggested that non-voltage-operated Ca^2＋ channels may have an important role in biphasic insulin secretion. CONCLUSION： Twelve major Ca^2＋ channel subunit types were identified in INS-1 and rat β cells and significant differences were observed in the expression of certain subunits between these cells.

FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts

AIM: To evaluate the efficacy and safety of the FOLFIRI regimen in patients with metastatic pancreatic adenocarcinoma (PAC) after the failure of gemcitabine and platinum salts. METHODS: All consecutive patients with histologically confirmed, metastatic PAC and World Health Organiza-tion performance status (PS) ≤ 2 received FOLFIRI-1 [irinotecan 180 mg/m2 on day 1 and leucovorin 400 mg/m2 followed by 5-fluorouracil (5-FU) 400 mg/m2 bolus, then 5-FU 2400 mg/m2 as a 46-h infusion, biweekly] or FOLFIRI-3 (irinotecan 100 mg/m2 on day 1 and leucovorin 400 mg/m2, then 5-FU 2400 mg/m2 as a 46-h infusion and irinotecan 100 mg/m2 repeated on day 3, biweekly) after failure of gemcitabine and platinum-based chemotherapies as a systematic policy in two institutions between January 2005 and May 2010. Tumor response, time to progression (TTP), overall survival rate (OS) and grade 3-4 toxicities were retrospectively studied. Subgroup analyses were performed to search for prognostic factors. RESULTS: Sixty-three patients (52.4% male, median age 59 years) were analyzed. Among them, 42.9% were PS 0, 38.1% were PS 1 and 19.0% were PS 2. Fifty one patients (81.0%) had liver metastases. Before the FOLFIRI regimen, patients had received 1 line (n = 19), 2 lines (n = 39) or 3 lines (n = 5) of chemotherapy. Median TTP obtained with the line before FOLFIRI was 3.9 mo (95% CI: 3.4-5.3 mo). A total of 480 cycles was completed (median: 6 cycles, range: 1-51 cycles). The main reason for discontinuing FOLFIRI was tumor progression (90.3%). Tumor control was achieved in 25 patients (39.7%) (partial response: n = 5, stable disease: n = 20) with FOLFIRI. Median TTP was 3.0 mo (95% CI: 2.1-3.9 mo) and median OS was 6.6 mo (95% CI: 5.3-8.1 mo). Dose adaptation was required in 36 patients (57.1%). Fifteen patients (23.8%) had grade 3-4 toxicities, mainly hematological (n = 11) or digestive (n = 4). Febrile neutropenia occurred in 3 patients. There was no toxic death. PS 2 was significantly associated with poor TTP [hazard ratio (HR): 16.036, P < 0.0001] and OS (HR: 4.003, P = 0.004). CONCLUSION: The FOLFIRI regimen had an acceptable toxicity and an interesting efficacy in our study, limited to patients in good condition (PS 0-1).

慢性胰腺炎胰腺结石病处理方式选择

胰腺结石病是慢性胰腺炎诊治过程中十分常见的一种病理形式,可简称为胰石病(症)。虽然在普通人群中发病率不超过1%,但在慢性胰腺炎患者群中却并不少见,其发病率可达50%以上[1]。临床所发现的胰腺结石病主要表现为两种形式:胰管结石和胰腺钙化。前者可称为真性结石,顾名思义,结石常发生于主胰管或主要分支胰管内,是胰腺结石病的常见表现形式(图1a)。中国慢性胰腺炎患者中约8.5%存在胰管结石,其中约40%仅发生于胰头部[2-3]。

丹参对胆源性胰腺炎的防治作用

目的 探讨胆源性胰腺炎 (BP)的发病过程中 ,胰腺泡细胞内游离钙离子 [Ca2 + ]i浓度的变化机制及丹参对BP的防治作用。方法 采用流式细胞仪 (FCM )和细胞内 [Ca2 + ]i探针Fluo 3 AM检测胆胰管结扎组 (A组 )及其加丹参组 (B组 ,丹参注射剂量为 5g/kg)、CCK OP静脉输液组 (C组 )及其加丹参组 (D组 )和对照组 (E组 )SD大鼠胰腺泡细胞内 [Ca2 + ]i浓度 ,并检测血淀粉酶、血清钙离子浓度及胰腺病理变化。结果 A、B、C组胰腺泡细胞内 [Ca2 + ]i浓度分别为 8.95± 1.0 6、4.73± 1.0 3、5 .6 7± 0 .98、4.5 0± 0 .6 3,血浆淀粉酶含量分别为 (2 0 972 .1± 32 98.7)U/L、(12 330 .2±2 6 77.7)U/L、(1815 8.0± 3795 .6 )U/L、(112 36 .2± 2 136 .2 )U/L ,胰腺重量分别为 (6 0 9.6 0±71.96 )mg、(492 .70± 31.96 )mg、(5 2 8.70± 80 .0 5 )mg、(437.70± 46 .5 6 )mg及胰腺组织学炎症记分(14、10、12、9)均明显高于E组 3.31± 0 .70、(6 895 .7± 11913.9)U/L、(370 .6 0± 42 .6 7)mg、0 (P <0 .0 5 ) ;A、C组高于B、D组 (P <0 .0 5 )。A、B、C、D、E组血清钙离子浓度分别为 (2 .5 4± 0 .0 6 )mmol/L、(2 .71± 0 .13)mmol/L、(2 .5 6± 0 .13)mmol/L、(2 .90± 0 .0 9)mmol/L、(3.0 3± 0 .10 )mmol/