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G Farkas

Publications and source records attributed to G Farkas.

At least 37 records · Page 2Linked to original sources
PubMed1998

Experimental acute pancreatitis results in increased blood-brain barrier permeability in the rat: a potential role for tumor necrosis factor and interleukin 6.

Pancreatic encephalopathy is a severe complication of acute pancreatitis. Proinflammatory cytokines may play a role in the development of multi-organ failure during pancreatitis. In the present study, we measured the changes in the blood-brain barrier (BBB) permeability concomitantly with the determination of serum tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels in rats before, as well as 6, 24 and 48 h after the beginning of intraductal taurocholic acid-induced acute pancreatitis. Cytokine concentrations were measured in bioassays with specific cell lines (WEHI-164 for TNF and B-9 for IL-6), while the BBB permeability was determined for a small (sodium fluorescein, molecular weight (MW) 376 Da), and a large (Evans' blue-albumin, MW 67000 Da) tracer by spectrophotometry in the parietal cortex, hippocampus, striatum, cerebellum and medulla of rats. The serum TNF level was significantly (P < 0.05) increased 6 and 24 h after the induction of pancreatitis, while the IL-6 level increased after 24 and 48 h. A significant (P < 0.05) increase in BBB permeability for both tracers developed at 6 and 24 h in different brain regions of animals with acute pancreatitis. We conclude that cytokines, such as TNF and IL-6, may contribute to the vasogenic brain edema formation during acute pancreatitis.

Amylases↗
PubMed1998

Beneficial effect of octreotide treatment in acute pancreatitis in rats.

CONCLUSIONS: Octreotide treatment contributes to the regulation of tumor necrosis factor (TNF) production in sodium taurocholate-induced acute necrotizing pancreatitis in rats. Owing to its complex effect, octreotide can partially ameliorate the deleterious consequences of acute necrotizing pancreatitis. Elevated TNF and interleukin-6 (IL-6) levels in the peritoneal fluid may be considered a consequence of the activation of peritoneal macrophages. BACKGROUND: The effects of octreotide on exocrine pancreatic function have been investigated in numerous studies, but little attention has been paid to its influence on cytokine production in acute pancreatitis. METHODS: Acute pancreatitis was induced by the retrograde injection of taurocholic acid into the pancreatic duct in male Wistar rats. Serum amylase activity, wet pancreatic weight/body weight (pw/bw) ratio, and TNF and IL-6 levels were measured. Four micrograms/kg of octreotide was administered subcutaneously at the time of induction of pancreatitis and 24 or 48 h later. Rats were sacrificed 6, 24, 48, or 72 h after the operation. RESULTS: The serum amylase level and pancreatic weight to body weight ratio were decreased significantly in the octreotide-treated group. The serum TNF level was decreased significantly in the octreotide-treated group as compared with the control group at 6, 24, and 48 h (0.6 +/- 1.5, 2.0 +/- 3.3, and 0 vs 50 +/- 15.5, 37.5 +/- 18.4, and 13.1 +/- 12.5 U/mL, respectively). The ascites TNF level was decreased to 0 in the octreotide-treated group and was elevated in the control group at 72 h (28.0 +/- 49.0 U/mL). IL-6 production in ascites was extremely high in both groups at 6 h (80,000 +/- 43,817 pg/mL and 58,500 +/- 33,335 pg/mL), but the difference was not significant.

Amylases↗
PubMed1998

Beneficial effects of pentoxifylline treatment of experimental acute pancreatitis in rats.

UNLABELLED: The purposes of this study were to determine the tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels after the induction of acute necrotizing pancreatitis, and to establish the effects of pentoxifylline on cytokine production. METHODS: acute pancreatitis was induced by the retrograde injection of 200 microliters taurocholic acid into the pancreatic duct in male Wistar rats. The serum amylase activity, the wet pancreatic weight/body weight ratio, and the TNF and IL-6 levels were measured. Seven mg/kg pentoxifylline were administered intraperitoneally at the time of operation 6, 12 or 24 h later. Rats were killed 6, 24, 48 or 72 h after the operation. RESULTS: the TNF bioassay revealed high levels of TNF (30.2 +/- 5.4 U/ml, 35.0 +/- 5.0 U/ml and 36.6 +/- 6.0 U/ml) in the control group at 6, 24 and 48 h and (54.1 +/- 20 U/ml and 10.9 +/- 4.2 U/ml) in the pentoxifylline-treated group at 6 and 24 h, respectively, whereas the level had decreased to zero in the pentoxifylline-treated group at 48 h. The IL-6 bioassay likewise demonstrated high levels of IL-6 in the control group at 48 h and in the pentoxifylline-treated group at 6 and 24 h, and markedly decreased levels in the pentoxifylline-treated group at 48 h (7083 +/- 2844 pg/ml, 6463 +/- 1307 pg/ml, 10,329 +/- 5571 pg/ml vs 137.5 +/- 85.5 pg/ml, respectively, P < 0.05). The high mortality observed in the pancreatitis group (43%) was decreased by pentoxifylline administration to 11%. CONCLUSION: these results demonstrate that pentoxifylline very effectively inhibits cytokine production in acute pancreatitis.

Acute Disease↗
PubMed1998

Progress in the management and treatment of infected pancreatic necrosis.

Infected pancreatic necrosis and sepsis are the leading causes of mortality in necrotizing pancreatitis. A review has been undertaken of the results of the past two decades relating to different surgical treatments of infected pancreatic necrosis. During the period 1978-85, the surgical treatment of necrotizing pancreatitis and its complications in our department consisted of the 'conventional' therapy (resection of the involved pancreatic tissue, or necrosectomy and drainage) in 61 patients, with a mortality rate of 36% (22 patients died). Since 1986, we have performed necrosectomy and other surgical interventions combined with continuous widespread lavage in 142 patients with infected pancreatic necrosis. The overall mortality decreased significantly to 6.3% (9 patients died). This result was achieved by means of aggressive surgical treatment, continuous, prolonged washing and suction drainage and supportive therapy, including immunonutrition, modifying the cytokine production and adequate antibiotic and antifungal medication. This surgical strategy provides the possibility for recovery in cases of necrotizing pancreatitis with septic complications.

Adult↗
PubMed1998

Albuminuria after fetal pancreatic islet transplantation: a 10-year follow-up.

AIM OF THE STUDY: The prevention of diabetic nephropathy is as yet an unresolved issue. The aim of our study was to assess the effects of transplantation of long-term cultured and cryopreserved fetal pancreas islets on metabolic control and the development of diabetic nephropathy. METHODS: Serum C-peptide, glucose, HbA1c, insulin requirements, urinary albumin excretion rate, and blood pressure of 10 insulin-dependent diabetic patients after transplantation were compared with a group of 27 insulin-dependent diabetic controls on insulin therapy only during a 10-year follow-up. RESULTS: In the first year after transplantation mean insulin requirement decreased from 53.6+/-2.2 to 35.8+/-1.2 units. C-peptide levels appeared (0.55+/-0.08 ng/ml) and remained detectable throughout the follow-up. Blood glucose and HbA1c were significantly (P<0.05) lower than in the controls. Mean albumin excretion rates of the transplant and the control groups during the follow up were 18.8+/-8.5 and 11.7+/-2.0, 16.6+/-6.6 and 14.0+/-2.3, 15.0+/-5.0 and 15.1+/-2.7, 15.3+/-7.5 and 20.4+/-4.2, 19.8+/-6.2 and 36.7+/-11.1, 11.7+/-3.6 and 51.3+/-14.6, 14.1+/-4.2 and 71.4+/-23.1, 22.7+/-8.6 and 92.0+/-28.1, 18.0+/-5.9 and 107.6+/-35.6, 21.7+/-11.0 and 101.5+/-29.3 microg/min respectively. From the 6th year the difference between the two groups was significant (P<0.001). In the transplant group initial mean systolic and diastolic blood pressure values were 132.0+/-3.3 and 81.5+/-1.5 mmHg, in the controls 130.4+/-3.4 and 79.6+/-1.6 mmHg respectively. Significant changes (P<0.05) of blood pressure during the follow-up or differences between the two groups were not observed. CONCLUSIONS: We conclude that fetal islet transplantation is effective in achieving good long-term diabetes control and in the prevention of diabetic nephropathy.

Adult↗
PubMed1997

Differential effects of tyrosine kinase inhibitors and an inhibitor of the mitogen-activated protein kinase cascade on degranulation and superoxide production of human neutrophil granulocytes.

The effects of two different tyrosine kinase inhibitors (genistein and erbstatin analog) and an inhibitor (2'-amino-3'-methoxyflavone; PD98059) of the mitogen-activated protein (MAP) kinase kinase on the primary granule exocytosis and superoxide (O2.-) production of human neutrophil granulocytes were compared. The effector responses induced by stimulation of the chemotactic receptors by formyl-methionyl-leucyl-phenylalanine and platelet-activating factor were blocked both by genistein and erbstatin analog. In contrast, degranulation and O2.- production triggered by the activation of protein kinase C with phorbol-12-myristate-13-acetate were reduced by erbstatin analog but not by genistein. This inhibitory pattern was observed in both effector responses, but the sensitivity of O2.- production toward tyrosine kinase inhibition was markedly higher than that of degranulation. PD98059 caused no considerable effect on any of the above responses. The data presented indicate that tyrosine kinases are involved not only in the respiratory burst but also in the organization of the degranulation response of neutrophil granulocytes. It is suggested that several tyrosine kinases of different inhibitor sensitivity may participate in the transduction of extracellular signals. However, activation of the MAP kinase cascade does not appear to be involved in either of the investigated biological responses of the neutrophils.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1997

[Management of diabetes induced by nearly total (95%) pancreatectomy with autologous transplantation of Langerhans cells].

The present report concerns a patient who had undergone nearly total pancreatectomy (95%) with pancreatic islet autotransplantation for intractable pain caused by obstructive chronic pancreatitis. Islets were prepared by a modified collagenase digestion and were cultured in vitro in Eagel's medium in 5% CO2 in air at 37 degrees C for 5 days. The resultant preparation, containing about 150,000 islets, was injected into the recipient's liver via the umbilical vein. No complication occurred from the pancreatectomy or transplant. Postoperatively, the patient had complete relief of the abdominal pain, and the insulin-independent condition remained with normal fasting blood glucose, and hemoglobin A1c for 11 months. Subsequently the fasting hyperglycemia was evident, and the patient began oral antidiabetic medication, but 2 year after transplantation the insulin-dependent condition demanded exogenous insulin (24 U). At present the fasting serum C-peptide level is 0.6 ng/ml and the HbA1c of 5.8% confirms the normoglycemic condition at the same insulin dose. Islet auto-transplantation should be considered as an adjunct procedure to prevent or ameliorate diabetes after total or nearly total pancreatic resection.

Adult↗
PubMed1997

[Cytokines in experimental acute pancreatitis].

The authors induced acute necrotizing pancreatitis in Wistar rat by intraductal injection of taurocholic acid (150 microliters or 200 microliters 6%). Plasma values of amylase, TNF, IL-6 levels and wet pancreas weight/body weight ratio have been determined. Histologic analysis of pancreas proved severe acute necrotizing pancreatitis with microabscess formation and beginning respiratory distress syndrome was observed in the lungs, TNF and IL-6 levels increased significantly after administration of 200 microliters 6% taurocholic acid. The authors emphasise the importance of cytokines in the development of acute necrotizing pancreatitis.

Amylases↗
PubMed1997

Gadolinium chloride-induced macrophage blockade prevents rejection of human insulinoma cell xenograft in rats.

The effect of gadolinium chloride (GdCl3)-induced Kupffer cell blockade on the survival of discordant insulinoma cell xenografts was investigated. Insulinoma cells isolated by means of collagenase from human insulinoma and subsequently cultured were transplanted through the portal vein into the liver of streptozotocin-induced diabetic, male, CFY inbred rats. In the control, streptozotocin-treated rats, the decrease in blood glucose level was only transitory, in contrast with the GdCl3-pretreated diabetic rats, which remained normoglycemic during the 2-week observation period. Histologically, in the liver and lung of rats pretreated with GdCl3, large areas of extensively proliferating insulinoma cells were seen, whereas no insulinoma cells were seen in either the liver or the lung of diabetic control rats, not treated with GdCl3. These studies suggest that the Kupffer cells play significant roles in the recognition of xenoantigens and the induction of xenograft rejection.

Animals↗
PubMed1997

Prognostic role of 99mTc-HM-PAO-leukocyte scintigraphy in acute pancreatitis and in patients with pancreatic pseudocysts.

Fifty-five leukocyte scintigraphies were performed. Thirty-five patients (group 1) with acute pancreatitis in the early phase and 20 patients (group 2) with pancreatic chronic pseudocysts following acute pancreatitis were tested. The clinical features, laboratory parameters, and Ranson classifications were registered during hospitalization. In group 1, most of the cases with a severe clinical outcome gave positive leukocyte scintigraphic results (10/12). Leukocyte accumulation was also detected in patients with mild acute pancreatitis (4/23), but at a lower frequency. In the acute phase, significant differences in laboratory parameters (sedimentation rate and leukocyte count) were found in the leukocyte scintigraphy-positive versus-negative cases. The scintigraphic activity correlated with the sedimentation rate, leukocyte count, fever, and duration of hospitalization. In group 2 there were five cases with a positive leukocyte scan. A pancreatic abscess was found in four of them during surgery. In seven patients with a normal scintigram, surgery revealed a noninfected pancreatic pseudocyst. Leukocyte infiltration of the pancreas can be demonstrated by leukocyte scintigraphy. A positive leukocyte scan indicated a severe course of acute pancreatitis. The method also seems useful for differentiation between infected and noninfected chronic pancreatic pseudocysts.

Acute Disease↗
PubMed1997

Effects of tumor necrosis factor and pentoxifylline on ICAM-1 expression on human polymorphonuclear granulocytes.

Intercellular adhesion molecule-1 (ICAM-1) is a cytokine-inducible adhesion molecule, expressed on cells of multiple lineages at the site of inflammation. Cytofluorometric analysis revealed that CD16-positive peripheral blood polymorphonuclear leukocytes (PMNs, neutrophils) expressed ICAM-1 on their surface, and it was upregulated by in vitro stimulation with tumor necrosis factor (TNF), GM-CSF and Staphylococcus aureus. The S. aureus-induced stimulation of ICAM-1 expression was inhibited by pentoxifylline (PTX). As TNF is a potent inducer of ICAM-1 expression, it is concluded that in these experiments the inhibition of TNF production by PTX concomitantly resulted in the inhibition of the upregulation of ICAM-1. However, the inhibition of granulocyte apoptosis by PTX might be of importance in this process. The present study provides evidence that cytokine-stimulated neutrophils are able to express the adhesion molecule ICAM-1 and this may allow ICAM-1-positive neutrophils to physically interact with LFA-1-positive inflammatory cells. The preliminary results demonstrate that the basal expression of ICAM-1 on PMNs of septic patients is higher than that in the case of normal blood donors. Further studies will elucidate the in vivo relevance of cytokine-induced neutrophil ICAM-1 expression and the potential role of its inhibition by PTX in inflammatory response disorders.

Apoptosis↗
PubMed1997

Relevance of cytokine production to infected pancreatic necrosis.

The purpose of this study was to evaluate the role of cytokines in septic conditions following acute pancreatitis and to elaborate a new strategy in the treatment. Increased TNF and IL-6 serum levels were found in 30% of the patients (n = 40), while the IL-6 level was elevated in all of them. There was a positive correlation between the serum IL-6 and sICAM-1 levels. The in vitro TNF and IL-6 producing capacities were initially higher in the study group, but decreased on subsequent days, especially in fatal cases (n = 3). Administration of pentoxifylline [PTX] (400 mg/day) to septic patients following necrotizing pancreatitis resulted in TNF and IL-6 production similar to that observed in control donors. The level of sICAM-1 also decreased following PTX therapy. These results suggest that cytokines produced by activated leucocytes are important in the pathogenesis of infected pancreatic necrosis, and their inhibition might be of therapeutic advantage.

APACHE↗
PubMed1997

TGF-beta 1 and IL-6--new aspects in pancreas regeneration?

Plasma levels of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta 1) were studied during cholecystokinin octapeptide (CCK-8)-induced regeneration after pancreas resection in rats. The weight of the pancreas and the DNA and protein contents increased significantly. The serum levels of TGF-beta 1 and IL-6 were increased significantly on days 7 and 14. There was no significant change in serum amylase levels. These findings indicate that cytokines such as TGF-beta 1 and IL-6 may play a role in the pathomechanism of pancreas regeneration.

Amylases↗
PubMed1997

Plasma levels of TNF and IL-6 following induction of acute pancreatitis and pentoxifylline treatment in rats.

Activation of cytokine cascade is a decisive factor in determining the pathobiology of different inflammatory processes including acute pancreatitis. The purposes of this study were to determine the TNF and IL-6 levels after the induction of acute necrotizing pancreatitis, and to establish the effects of pentoxifylline on the cytokine production and the severity of pancreatitis. Acute necrotizing pancreatitis was induced by the retrograde injection of 200 microliters taurocholic acid into the pancreatic duct in male Wistar rats. TNF was titrated in a bioassay on cell line WEHI clone 164. IL-6 was measured via its proliferative action on the IL-6 dependent mouse hybridoma cell line B-9. Seven mg/kg pentoxifylline was administered intraperitoneally at the time of operation and/or 24 hours later. Rats were sacrificed, 48 or 72 hours after the operation. The TNF bioassay revealed high levels of TNF (36.6 +/- 6.0 U/ml) in the control group whereas levels decreased to zero in the pentoxifylline-treated group. The IL-6 bioassay likewise demonstrated high levels of IL-6 in the control group and markedly decreased levels in the pentoxifylline treated group (7083 +/- 2844 pg/ml, 6463 +/- 1307 pg/ml vs. 137.5 +/- 85.5 pg/ml, respectively, p < 0.05). The high mortality observed in the control group (43%) was sharply decreased by pentoxifylline administration to 11%. The data suggest that pentoxifylline is capable of modifying the cytokine production after 48 hours of induction of acute pancreatitis.

Amylases↗
PubMed1996

Surgical strategy and management of infected pancreatic necrosis.

Infected pancreatic necrosis and sepsis are the leading causes of death in patients with necrotizing pancreatitis. Between 1986 and 1993, 123 patients with infected pancreatic necrosis were treated; in all cases the infected necrosis extended to the retroperitoneal area. Surgical treatment was performed a mean of 18.5 days after the onset of acute pancreatitis. Operative management consisted of wide-ranging necrosectomy through all the affected area, combined with continuous widespread lavage and suction drainage applied for a mean of 39.5 days, with a median of 6.5 litres of normal saline per day. In 56 cases (46 per cent), another surgical intervention (distal pancreatic resection, splenectomy, cholecystectomy, sphincteroplasty or colonic resection) was also performed. Bacteriological findings revealed mainly enteric bacteria, but Candida infection was detected in 21 per cent of patients. The overall hospital mortality rate was 7 per cent (nine patients died). Infected pancreatic necrosis responds well to aggressive surgical treatment, continuous, long-standing lavage and suction drainage, together with supportive therapy combined with adequate antibiotic and antifungal medication.

Acute Disease↗
PubMed1996

Time-course changes in serum cytokine levels in two experimental acute pancreatitis models in rats.

Activated leukocytes and cytokines have important roles in the multi-system involvement during acute pancreatitis. The changes in the serum level of tumor necrosis factor-a (TNF-alpha) and interleukin-6 (IL-6) over time were investigated in two experimental acute pancreatitis models in rats. Mild edematous pancreatitis was induced with an overdose of cholecystokinin octapeptide (CCK-8), while a severe hemorrhagic form of pancreatitis was induced by ligation of the common bilio-pancreatic duct. The rats were examined 2, 4, 8, 16, 24 and 48 h after pancreatitis induction. The severity of the inflammation was assessed by measurement of the serum amylase activity, quantification of the edema, and histological examination. Serum TNF-alpha and IL-6 were determined by bioassay, using the TNF-sensitive WEHI 164 and the IL-6-dependent B9 cell lines, respectively. In CCK-8-induced acute pancreatitis, the pancreatic weight/body weight ratio (pw/bw) and amylase level were significantly elevated at 2 h, and the maximum levels were observed at 4 h (8.19 +/- 1.13 mg/g and 69.4 +/- 12.8 x 10(3) U/ml, respectively). Both parameters subsequently decreased continuously during the observation period. The serum IL-6 level was significantly increased at 4 h relative to the controls (123.3 +/- 5.8 vs 37.5 +/- 15 pg/ml), and then decreased continuously. In this model, only a moderate level of serum TNF-alpha was observed at 2 h. In the biliary type of acute pancreatitis, the ratio pw/bw increased continuously during the study and reached the maximum level at 48 h relative to the sham-operated control (8.8 +/- 1.4 vs 5.3 +/- 0.8 mg/g). The serum amylase level was significantly elevated at 2 h (43.2 +/- 13 x 10(3) U/ml), but then decreased continuously. The serum IL-6 reached its maximum level at 16 h (3800 +/- 447 pg/ml). In this model, increased TNF-alpha levels (75-300 U/ml) were measured 8, 16 and 24 h after pancreatitis induction. The results led to correlations between the serum IL-6 levels and the biochemical and morphological severity of acute pancreatitis in both experimental models. The data suggest that IL-6 and TNF-alpha may participate in the pathogenesis of these types of acute pancreatitis.

Acute Disease↗
PubMed1996

Possible involvement of protein kinase C-epsilon in phorbol ester-induced growth inhibition of human lymphoblastic cells.

Sustained activation of members of the protein kinase C (PKC) family is known to influence the growth and differentiation of various cell types, however, the specific roles for individual isoforms mediating these cellular events have yet to be elucidated. Activation of PKC by phorbol esters leads to growth inhibition in certain cell lines. The HT58 human B lymphoblastic cell may serve as a cellular model system to investigate the participation of individual isoforms in the initial events of growth arrest induced by phorbol ester. Determination of cell cycle and investigation of apoptosis were performed by flow cytometric measurements. Phorbol ester-induced translocation and down-regulation of the conventional alpha, beta and the novel epsilon isoforms of PKC were demonstrated by Western blot analysis. At lower concentrations (o.5 ng/ml) phorbol myristate acetate (PMA) stimulated a G1 arrest with retention of viability in the human HT58 B lymphoblastic cell. The protein kinase inhibitor staurosporine at a concentration of 25 nM did not significantly alter HT58 cell viability. However, staurosporine (25 nM) induced apoptosis in cells preincubated for 4 hr with 0.5-1.0 ng/ml PMA. The translocation of PKC-epsilon was observed within 39 min exposure to 0.5 ng/ml PMA. After a 4 hr treatment, evidence for down-regulation and and altered phosphorylation state of PKC-epsilon was seen. In contrast, the conventional alpha and beta isoforms were practically uneffected by this PMA treatment. At higher PMA concentrations (50 ng/ml) the alpha and beta isoforms showed a significant down-regulation. The preferential alterations in PKC-epsilon observed under the conditions required for PMA to influence the growth and survival of HT58 cells suggest a role for the Ca(2+)-independent epsilon isoform in mediating the initial events of the phorbol ester stimulated cellular responses.

Apoptosis↗