ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Recent investigations indicated that hyperthermia has antitumor effects. Several interstitial hyperthermic techniques were developed, and their clinical usefulness and safety were evaluated. However, few authors have attempted to study the use of interstitial hyperthermia for the treatment of pancreatic carcinomas. Therefore the efficacy of local selective thermocoagulation by radiofrequency was evaluated in 20 patients with unresectable carcinomas of the pancreas. A laparotomy and radiofrequency heating were performed in 20 patients with unresectable pancreatic carcinomas after informed consent. Local heat coagulation was induced by a 13.56-MHz radiofrequency pulse, produced by the heating apparatus. Four 2-cm needle electrodes were placed in the tumor, in a square array, at intervals of 2 cm. The heat was then administered for 15 min at a controlled temperature of 50°C in the radiofrequency field (2 × 2 × 2 cc). All the patients were evaluated by computed tomographic scanning. Tumor markers in the blood also were assayed before and after the heating. Follow-up computed tomographic scans demonstrated that the tumor mass was enhanced heterogeneously, and after selective thermocoagulation, images revealed a change to a homogeneous low-density area. The blood levels of tumor markers decreased to below pretreatment values in 15 patients. Of the 20 cases treated with thermocoagulation, two had critical complications. One patient had septic shock, and another had gastrointestinal bleeding. The other 18 patients had no significant complications. These observations suggest that the selective thermocoagulation of tumor tissues using this equipment was relatively safe. These results justify further clinical trials for the treatment of patients with unresectable tumors without metastasis, or patients with benign pancreatic tumors such as insulinomas.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Metallothioneins (MTs) are small intracellular proteins that bind to metal ions and are involved in heavy-metal homeostasis and detoxication. Pancreatic islets were previously reported to contain zinc-containing matrix metalloproteinases (MMPs) and inhibitors of metalloproteinases (TIMPs) by immunocytochemical staining. The immunolocalization of MMPs and TIMPs in pancreatic islets prompted us to investigate further the link between zinc and MTs. Both beta and nonbeta islet cells were found to contain MTs by this immunocytochemical staining, suggesting that MTs may be involved in pancreatic hormone synthesis and secretion, in addition to their roles in zinc homeostasis and detoxification.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Diabetes mellitus secondary to chronic pancreatitis is characterized by a progressive destruction of the pancreas, including loss of the islet cells, leading to a form of diabetes that can mimic both type 1 and type 2 diabetes. Glucagon-like peptide 1(7-36)amide (GLP-1), an intestinally derived insulinotropic hormone, represents a potential therapeutic agent for type 2 diabetes, because exogenous GLP-1 has been shown to increase the insulin and reduce the glucagon concentrations in these patients, and thus induce lower blood glucose, but without causing hypoglycemia. Ten patients with diabetes mellitus secondary to chronic pancreatitis and five normal subjects were studied. Nine patients were treated with insulin and one patient with sulfonylurea. In the fasting state, saline or GLP-1 in doses of 0.4 or 1.2 pmol/min/kg body weight were infused intravenously for 4 hours. Blood glucose was reduced in all patients with both doses of GLP-1; plasma C-peptide increased (p< 0.02), and plasma glucagon decreased (p< 0.02) compared with basal levels, also in three patients with normoglycemia and high levels of presumably exogenous insulin. Similar results were obtained in the normal subjects. In conclusion, GLP-1 treatment may be considered in patients with diabetes mellitus secondary to chronic pancreatitis, provided that a certain amount of &agr;- and &bgr;-cell secretory capacity is still present.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Reversible protein phosphorylation is an important mechanism by which cells transduce external signals into biologic responses. Levels of protein phosphorylation are determined by the balanced actions of both protein kinases and protein phosphatases (PPases). However, compared with protein kinases, regulation of PPases has been relatively neglected. The insulin secretagogue l-arginine, an immediate metabolic precursor to polyamines, causes a rapid and transient decrease in PPase-1 activity in insulin-secreting RINm5F cells. We here show that polyamines dose-dependently suppress PPase-1-like activity when added to RINm5F cell homogenates at physiologic concentrations (spermine > spermidine > putrescine), while having minor and inconsistent effects on PPase-2A-like activity. The IC50value for spermine on PPase-1-like activity was ≈4 mM. The inhibitory effect was reproduced and of comparable magnitude on purified PPases types 1 and 2A. On the other hand, when endogenous polyamine pools were exhausted by 4 days of exposure to the specific l-ornithine decarboxylase inhibitor dl-&agr;-difluoromethylornithine, there was an increase in PPase-2A-like activity. Quantitative Western analysis revealed that the amount of PPase-2A protein did not change after this treatment. It is concluded that polyamines cause time-and concentration-dependent inhibitory effects on RINm5F cell PPase activities, which may contribute to the increase in phosphorylation state that occurs after secretory stimulation.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Insulin-releasing effects of 2-ketobutyric acid (KB), 2-ketoisocaproic acid (KIC), 2-keto-3-methylvaleric acid (KMV), and 3-phenylpyruvic acid (PP) were examined by using clonal beta cells. Whereas KIC, KMV, and PP dose-dependently initiated insulin secretion and potentiated the effects of 4.2–16.7 mMglucose, equimolar KB was without effect. Transport inhibition by using 10 mMvaline, isoleucine, 2-cyano-3 hydroxycinnamate or 2-cyano-4 hydroxycinnamate, or metabolic inhibition by 15 mMmannoheptulose, 5 mMsodium azide, 5 mMsodium cyanide, or removal of HCO3reduced the secretory effects of KIC, KMV, and PP. Whereas K+depletion reduced keto acid–induced insulin output, depolarizing concentrations of l-leucine and l-arginine potentiated the keto acid–induced effects. Under depolarizing conditions (25 mMKCl and 16.7 mMglucose), 10 mMKIC, KMV, or PP induced insulin secretion, suggesting KATPchannel–independent actions. Furthermore, the KATPchannel opener diazoxide reduced, but did not abolish, the keto acid–induced effects. However, voltage-dependent Ca2+channel blockade with verapamil or removal of extracellular Ca2+abolished keto acid–induced insulin release. Collectively, these results indicate that KIC, KMV, and PP initiate insulin secretion at least partially independently of KATPchannel activity, through both mitochondrial metabolism and regulation of Ca2+influx.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Because the development of insulitis and diabetes is predictable inLyp/Lypcongenic BB rats, we have characterized early islet inflammation in these rats to determine the cell subsets involved in the onset of autoimmune insulitis. Pancreas sections from prediabeticLyp/Lyp, Lyp/+ and +/+ rats were analyzed by immunohistochemistry. We found W3/25+ cells in the exo-and endocrine tissue from all three genotypes, but intraislet insulitis was never found inLyp/+ or +/+ rats. The onset of massive, intraislet B- and T-cell infiltration inLyp/Lyprats was preceded byRelB+ cells in and around the islets, followed by ED1+ monocytes/macrophages.RelB+ cells were more frequent in the parafollicular cortex of pancreatic lymph nodes fromLyp/Lypthan fromLyp/+ and +/+ rats. In theLyp/Lypthymus, we found significantly increased expression of IL-12p40 messenger RNA (mRNA;p< 0.001), located in theRelB-protein-rich corticomedullary junction. The NF-&kgr;B/RelB complex specifically transactivates genes involved in antigen presentation in dendritic cells.RelB+ cells in the islets may therefore mark the onset of autoimmune insulitis and antigen-specific activation of autoreactive T cells in the lymph nodes of diabetes proneLyp/LypBB rats. In the thymus,RelB+ cells may support theLyp-dependent development of self-reactive thymocytes by activation of cytokine expression.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Oral administration of relevant autoantigens is being considered as a realistic approach for the prevention of several autoimmune diseases. In this study we administered, orally, to young female NOD/Ak mice (diabetes incidence, 40%) and NOD/LtJ mice (diabetes incidence, 70%) whole pancreatic extract on days 19, 20, 21, 22, 23, 26, and 27 and studied its effects on the development of diabetes until day 250. The cumulative incidence of diabetes in both the colonies after pancreatic extract treatment was compared with the incidence after oral administration of syngeneic liver extract or in untreated mice. In the NOD/Ak mice, the incidence of diabetes in the pancreatic extract group was significantly lower (6%;n= 34,p= 0.004) and was delayed compared with 33% in the liver group (n= 34) and 44% in the untreated group (n= 18). Significant protection from diabetes and a delay in its onset also were observed in the NOD/LtJ mice treated with pancreatic extract (16%;n= 19,p= 0.002) compared with those liver extract treated (72%;n= 18) and in untreated mice (60%;n= 22). Pancreatic histology at day 90 from all the study groups showed that the protection from diabetes in the pancreatic-extract group was not associated with reduced insulitis. We speculate that the marked disease protection observed in this study with orally administered pancreatic extract may be associated with the presence of immunoregulatory cells with a predominant Th2 cytokine bias. Our studies may have implications for the prevention of insulin-dependent diabetes mellitus (IDDM) in humans.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Arginine-induced pancreatic acinar cell injury has been reported in vivo, but the mechanism involved is unknown. In this study we investigated the effects of arginine on the cell morphology and pancreatitis-associated protein (PAP) gene expression in rat pancreatic acinar AR4-2J cells in vitro. Arginine inhibited the proliferation of AR4-2J cells in a dose-dependent manner. This decrease in proliferation was due to an increase in apoptosis, as assessed by cell morphology and DNA fragmentation. PAP messenger RNA (mRNA) was expressed at doses of 2.5 and 5.0 mg/ml of arginine, and a time-course study showed that the expression started 2 h after arginine addition and peaked at 6 h. Apoptosis was rarely seen when PAP mRNA was highly expressed, but occurred when PAP mRNA expression was decreased. These results suggest that arginine induces apoptosis and PAP gene expression in pancreatic acinar cells and that PAP might inhibit the induction of apoptosis.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

These studies investigated the growth characteristics and functional properties of isolated canine pancreatic ductal epithelial cells. Cells were isolated from the accessory pancreatic duct and cultured by using three conditions: on vitrogen-coated petri dishes with fibroblast conditioned medium (nonpolarized); in vitrogen-coated Transwells above a fibroblast feeder layer (polarized); or as organotypic rafts above a fibroblast-embedded collagen layer (polarized). Growth characteristics, transepithelial resistances, and carbonic anhydrase and cyclic adenosine monophosphate (AMP) responses were evaluated. Under polarized conditions, the cells grew as monolayers with columnar epithelial characteristics. The monolayers developed high transepithelial resistance and became impervious to the passage of horseradish peroxidase. Epithelial growth factor (EGF) (2 ng/ml) stimulated ductal cell growth and accelerated the formation of a high-resistance monolayer. Forskolin (10 &mgr;M) rapidly decreased transepithelial resistance. Carbonic anhydrase activity, which was lower in nonpolarized compared with polarized conditions, was stimulated by carbachol (175 &mgr;M). Secretin, however, did not stimulate carbonic anhydrase activity in these cells. Although secretin stimulated adenylyl cyclase activity in early-passage cells, this response was lost in later-passage cells. Both vasoactive intestinal polypeptide (VIP; 1 &mgr;M) and forskolin (10 &mgr;M) consistently increased adenylyl cyclase activity. Isolated canine pancreatic ductal epithelial cells proliferate in vitro, develop high-resistance epithelial monolayers, and respond to stimuli that activate adenylyl cyclase. These cells should provide a useful model for regulatory studies of ductal cell functions.

ISSN:0885-3177    

出版商:OVID    

年代:2000

数据来源: OVID