ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The epidermal growth factor (EGF) receptor is overexpressed in human pancreatic cancers and cultured cell lines. TP40 is a chimeric protein composed of transforming growth factor-α (TGF-α) linked to a modifiedPseudomonasexotoxin A (PE40) that exerts growth inhibitory effects on cells bearing a high number of EGF receptors. Therefore, we compared the effect of TP40 on the growth of Chinese hamster ovary (CHO) cells expressing varying levels of the EGF receptor and on the growth of two human pancreatic cancer cell lines. The growth of CHO cells devoid of endogenous EGF receptors was minimally altered by high concentrations of TP40, even following a 72-h incubation period. In contrast, in CHO cells expressing ∼95,000 and 438,000 EGF receptors per cell, one-half maximal growth inhibition occurred at 5 and 3 ng/ml TP40, respectively. Following a 72-h incubation in T3M4 and COLO 357 human pancreatic cancer cells, one-half maximal growth inhibition occurred at 0.2 and 0.4 ng/ml TP40, respectively. This effect was significantly greater than that of nativePseudomonasexotoxin A. These findings indicate that human pancreatic cancer cells are markedly sensitive to the growth inhibitory effects of TP40 and raise the possibility that TP40 may have a therapeutic role in this disorder.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Tumor necrosis factor-α (TNFα) has been implicated as one of the numerous likely mediators of the systemic complications of acute pancreatitis. Recent suggestions that calcium (Ca2+) acts as a signal not only for TNFα release but also for TNFα action at distant sites led us to hypothesize that the calcium channel blocker diltiazem could inhibit TNFα release in acute pancreatitis, ameliorating the severity of the disease and improving overall survival. A rat model of acute pancreatitis induced by retrograde ductal infusion of bile was used for two experiments (n= 120). Experiment 1 was designed to determine the effects of calcium channel blockade using diltiazem on the severity of pancreatitis as measured by changes in biochemistry, pathology, and serum TNFα levels. In experiment 2, effects of calcium channel blockade on animal survival were measured over 72 h. Calcium channel blockade was associated with a significant reduction in serum TNFα levels as well as amelioration of pancreatitis by biochemical and pathological criteria. Overall survival from bile-induced pancreatitis was dramatically improved in rats pretreated with diltiazem (80%) compared to untreated animals (40%). Our data suggest that calcium channel blockade is associated with TNFα inhibition and improved outcome in a rat model of acute pancreatitis.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Tumor necrosis factor (TNFα) has been shown to inhibit insulin release and it has been postulated to be an important effector in islet rejection. We studied the effect of cryopreservation on glucose oxidation rate (GOR), lipid synthesis, hormone secretion (insulin, glucagon, somatostatin, thyrotropin-releasing hormone), and cyclic guanosine 3',5'-monophosphate (cGMP) content of human islets, in the presence or absence of TNFα, looking for changes that could explain a different susceptibility to rejection for cryopreserved islets. Islets were isolated from multiple organ donor pancreata by collagenase digestion. The islets were then cultured for 7 days, cryopreserved (−0.25°C/min), and stored in liquid N2. After 24 h of culture, thawed islets were cultured for another 24 h in the presence or absence of TNFα. Islets were then washed to remove the cytokine and incubated in Krebs-Ringer bicarbonate (5 or 20 mMglucose), and both the cGMP content of the islets and the hormone concentration in the medium were determined by radio-immunoassay. GOR was measured as the production of14CO2from 5 or 20 mMD[U-14C]glucose, and de novo lipid synthesis was determined as D[U-14C]glucose incorporation into different lipidic fractions. Cryopreservation did not significantly modify the hormone response to glucose but it partially reversed the TNFα-induced inhibitory effect on insulin release in the presence of 20 mMglucose. In addition, the inhibitory effect of TNFα on phosphatidylcholine labeling was attenuated in cryopreserved islets compared with noncryopreserved islets. TNFα significantly stimulated islet nitrite production and cGMP accumulation, both effects being of a similar magnitude in cryopreserved and noncryopreserved islets. Our results suggest that cryopreservation can modify the metabolic and hormone response of human islets to TNFα. This effect is not mediated by changes in the TNFα-induced islet nitric oxide production or cGMP accumulation.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Partial obstruction of the adult hamster pancreas leads to islet cell differentiation and new islet formation. From morphologic and morphometric observations, we have tentatively identified the source of the new islet tissue to be from cells in the ducts. In this study, in vivo labeling with a single pulse of tritiated thymidine after partial duct obstruction was used to ascertain whether newly formed islet cells were in fact derived from cells in the ductal epithelium. Supportive evidence for this formulation was also sought using immunocyto-chemistry for islet hormones and in situ hybridization for glucagon and insulin mRNA to probe areas of proliferating duct cells. Endocrine cell differentiation was observed as a migration of cells out from small ducts beginning at about 10 days after obstruction. Duct and islet cell labeling indices (LI; %) in control animals remained at a low level (0.35 ± 0.01 and 0.36 ± 0.03, respectively) throughout the experiment. In contrast, at 2 weeks after partial obstruction, the duct and islet cell LI were 4.2 ± 0.7 and 0.80 ± 0.1 (p< 0.05 vs. control). After 2 weeks, there was a rapid and significant 86% decline in the duct cell LI to a low of 0.6 ± 0.2 at 8 weeks, which was accompanied by a comparable, but reciprocal, 113% increase in the islet cell LI to a high of 1.7 ± 0.8 (p< 0.05). In situ hybridization demonstrated glucagon and insulin mRNA-positive cells within intralobular ducts as early as 6 and 8 days, respectively, after obstruction. Glucagon and insulin peptides appeared in these cells at ∼8 and 10 days, respectively, as cells migrated out from the duct wall. This study provides additional evidence that further supports our concept that pancreatic endocrine cell differentiation in this model reiterates the normal ontogeny of β cell differentiation from cells in the ductular epithelium.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Primary culture of rat islets of Langerhans lose glucose responsiveness and eventually die when cultured for a long period of time. In this study we evaluated the effect of matrigel, a basement membrane extract, on (i) islet cell survival, (ii) cell responsiveness following a glucose challenge, and (iii) mRNA levels for insulin, glu-cagon, and somatostatin. Pancreatic islets were isolated by collagenase digestion and plated in culture dishes either coated or not with a matrigel layer. Using the reverse hemolytic plaque assay, we determined the total number of insulin-secreting cells and the amount of insulin secreted by individual beta cells. After 1 h of exposure to 5 mMglucose, β cells from 6-month-old rat islets cultured for 6 weeks on matrigel showed an equal number of insulin-secreting cells compared to freshly isolated islets cultured for only 3 days in the absence of matrigel (39.5 ± 2.5 vs. 37.1 ± 9.6%). Furthermore, the release of insulin by cells cultured on matrigel for 6 weeks increased in a glucose-dependent manner (p< 0.001) and showed an ED50of 7 mM. However, the amount of insulin released per single β cell was reduced by 40–60% (p< 0.02) compared to that released from isolated β cells derived from a 3-day culture of islets. Finally, there was a 35–55% increase (p< 0.05) in the levels of insulin, glucagon, and somatostatin mRNAs in cells cultured for 6 weeks on matrigel. These data suggest a trophic effect of matrigel on the maintenance of normal β-cell activity and function and may lead the way to the development of a new model for the study of pancreatic islets in long-term culture.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Preoperative radiological localization of insulinomas often fails because of the small size of the tumors. We studied retrospectively the value of different procedures in preoperative localization of insulinomas in 18 patients. Radiological assessment included transab-dominal ultrasonography, computed tomography, angiography, magnetic resonance imaging, transhepatic venous sampling, and endoscopic ultrasonography (EUS) for the last 11 patients. During surgery, the association of palpation and intraoperative ultrasonography localized 16 solitary tumors and two multiple tumors (mean size, 1.8 ± 1.1 cm). Three insulinomas were found to be malignant. Conventional preoperative methods correctly localized the tumor in seven of 18 cases (38%), whereas the sensitivity of EUS was 10 of 11 cases (90%). Surgical procedures involved eight enucleations, nine distal pancreatectomies, and one total pancreatectomy. Because of its high sensitivity and safety, EUS was found to be the best method for preoperative localization of insulinomas, and we recommend that EUS replace conventional methods for the majority of cases.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The pancreas commonly reacts to endoscopic papillosphincterotomy (EST) with a rise in serum amylase, and acute pancreatitis may also develop. The long-acting somatostatin analogue octreotide has recently been proposed for prevention of colangiopancreatography (ERCP)/EST-induced pancreatic reaction. Therefore, we tested the prophylactic effects of a subcutaneous 3-day administration of octreotide to 60 consecutive patients undergoing ERCP and EST. They were randomly allocated to receive either 200 μg octreotide t.i.d. for 3 days (30 cases) or placebo (control group, 30 cases) before the procedure. On the day of the examination, serum amylase levels were determined at baseline and 2, 4, 8, and 24 h thereafter. In the patients as a whole, the increases were statistically significant at 4 h (p< 0.01) and 8 h (p< 0.01). Epigastric pain occurred in 2 patients in the octreotide group and in 13 control subjects (p< 0.001). Even in some patients who had had previous episodes of relapsing pancreatitis, the rise in serum amylase was significantly lower in the octreotide group than in the control group at 4 h (p< 0.01), 8 h (p= 0.05), and 24 h (p= 0.05). Our data suggest that 3 days of prophylactic treatment with octreotide is effective for reducing the rise in serum amylase after EST/ERCP and could be proposed for patients with relapsing pancreatitis and other risk conditions before the Vater's papilla manipulation.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In humans chronic obstructive pancreatitis (COP) is thought to be a disease devoid of ductal stones. The aim of this study was to verify the presence and frequency of calcifications in patients with COP and compare them with those found in patients with chronic cal-cifying/calcific pancreatitis (CCP). We conducted a retrospective ERCP investigation in 115 patients with documented chronic pancreatitis. Only 75 could be safely classified as COP or CCP. Fifty-three patients (M:F ratio, 5.6:l; mean age, 36.1 ± 12.2 years) had CCP, 46 of whom (86.8%) with calcifications. Twenty-two patients (M:F ratio, 3.4:l; mean age, 45.3 ± 16.3 years;p< 0.05 vs. CCP) presented COP at endoscopic retrograde cholangiopan-creatography. 8 (36.4%) with ductal calcifications (p< 0.0001 vs. CCP). COP was secondary to acute pancreatitis in nine cases, to odditis in 11 cases, and to malignant tumor and hypertrophy of Oddi's sphincter, respectively, in the other two cases. The two patient groups showed no significant differences in drinking and smoking habits, number of painful relapses, disease duration, and incidence of diabetes, gallstones, and need for surgery. In conclusion, formation of ductal stones is by no means rare in COP and should be classified as a form of lithiasic pancreatitis. Early restoration of pancreatic outflow by removing the obstruction, or by shunt-type operations and abstinence from drinking and smoking, should resolve this type of disease.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The effect of oral administration of protease inhibitor (camostat) on pancreatic morphology and exocrine function (conscious rat model) was investigated using WBN/Kob rats with spontaneous chronic pancreatitis. In nontreated WBN/Kob rats (2–12 months of age), pancreatic fibrosis and parenchymal destruction compatible with human chronic pancreatitis appeared at 3 months and advanced with each month. Pancreatic secretion was markedly impaired at all ages. In WBN/Kob rats fed diets containing camostat (from 2–3 or 4–5 months of age), the pancreas was hypertrophic and did not show any histological appearances compatible with chronic pancreatitis, and moreover, exocrine function was thoroughly restored with increased plasma cholecystokinin concentrations. Oral administration of protease inhibitor has both preventive and therapeutic effects on pancreatic lesions and dysfunction in an animal model of chronic pancreatitis, probably via endogenous cholecystokinin release.

ISSN:0885-3177    

出版商:OVID    

年代:1996

数据来源: OVID