Biomedical subjects

Ernst von Dobschuetz

Publications and source records attributed to Ernst von Dobschuetz.

11 recordsLinked to original sources

PubMed2006

Targeting vascular endothelial growth factor pathway offers new possibilities to counteract microvascular disturbances during ischemia/reperfusion of the pancreas.

BACKGROUND: It is of crucial importance to explore new therapeutic strategies capable of combating or even preventing pancreatic graft failure after transplantation caused by ischemia reperfusion damage. So far, the role of the hypoxia induced mediator vascular endothelial growth factor (VEGF) upon pancreatic microcirculation has not been described. Therefore the aim of this study was to investigate its influence, using the novel tyrosinekinase inhibitor PTK787/ZK222584 (PTK/ZK), upon functional capillary density (FCD), leukocyte-endothelium interaction (LEI), and macromolecular permeability (P) of normal and postischemic pancreas tissue. METHODS: Sprague-Dawley rats were anesthetized and randomly assigned to five groups (n=7/group): (a) sham, (b) ischemia/reperfusion (I/R) control, (c) I/R and PTK/ZK treatment, (d) VEGF-superfusion, (e) VEGF-superfusion and PTK/ZK-treatment. A recently established method of digital dynamic intravital epifluorescence microscopy was used for evaluating the effective microvascular permeability together with FCD and LEI. RESULTS: Comparison between sham vs. I/R shows a significant upregulation of VEGF-expression followed by deterioration of microcirculation with decreased FCD, increased P and LEI. Treatment with PTK/ZK resulted in a significant decrease of P under conditions of superfusion with VEGF as well as I/R compared to corresponding groups without treatment. CONCLUSION: VEGF plays a crucial causative role involving an increase in permeability in normal as well as in postischemic pancreatitis via tyrosinkinase receptors. VEGF seems to be partly accountable for a deterioration of FCD and an upregulation of LEI via VEGF-tyrosinekinase receptor independent mechanisms. VEGF might be a promising potential therapeutic target in order to minimize edema formation caused by I/R and pancreatitis in pancreas transplantation.

Animals↗

PubMed2006

Nonoperative treatment of 15 benign esophageal perforations with self-expandable covered metal stents.

BACKGROUND: Spontaneous or iatrogenic esophageal perforations after endoscopic procedures are potentially life-threatening events with a considerable mortality rate. The aim of this study was to demonstrate that a nonoperative endoscopic treatment with self-expanding metal stents may have a lower morbidity and mortality rate compared with surgical treatment. METHODS: A nonrandomized observational study was conducted with 15 consecutive patients between January 1997 and June 2004. Benign spontaneous and iatrogenic esophageal perforations after endoscopic procedures were treated with self-expandable metal stents. RESULTS: Seven patients (group 1) underwent stent insertion with an average time delay of 45 minutes. In 8 patients (group 2), the median delay was 123 hours. All patients in group 1 had an uneventful recovery and left hospital 5 days (range, 3 to 9) after stent insertion. One patient in group 2 (1 of 8) died of pneumonia after 6 days. In any other cases, perforations healed successfully after stent placement, but the clinical course was generally complicated with sepsis and multiple organ failure. The average hospital stay was 44 days (range, 15 to 70). CONCLUSIONS: Immediate insertion of a self-expandable metal stent enables an excellent outcome with minimal mortality and morbidity without the need for operation. Even in cases of old esophageal perforations, sealing with self-expandable metal stents is still a good option although the clinical course is much less impressive than in early treated perforations.

Adult↗

PubMed2004

Giant ancient schwannoma of pancreatic head treated by extended pancreatoduodenectomy.

We report a case of a 55-year-old woman who was transferred from another center to our university clinic after diagnostic laparotomy with a pancreatic head tumor which was seen to encase the portal vein. Although intraoperative biopsies were performed, a histologic diagnosis of the tumor was not possible before giving suspect to a malignant tumor being resectable only with a vascular resection. In a second operation we performed a pylorus-preserving pancreatoduodenectomy. Due to adhesion of the tumor to the portal vein, a segmental resection and end-to-end anastomosis of the portal vein was necessary. Postoperative histologic diagnosis revealed an ancient schwannoma which was removed in toto being a rare report of this benign tumor in the pancreatic head. Ten months after the operation the patient is without any health problems. Partial resection of the portal vein, which is considered to be a safe procedure in high volume centers, stands in contrary to surgical nihilism of pancreatic head tumors suspecting advanced tumors with vascular involvement.

Female↗

PubMed2004

Ischemic preconditioning fails to improve microcirculation but increases apoptotic cell death in experimental pancreas transplantation.

Brief periods of warm ischemia and subsequent short reperfusion before either long-term cold or warm ischemic insult (ischemic preconditioning, IPC) have proven to ameliorate ischemia/reperfusion (I/R) injury in various organs, such as the liver and lung. The aim of this study was to examine the effect of IPC on pancreatic cell apoptosis and microcirculatory impairments in experimental pancreas transplantation. Male Lewis rats served as donors and recipients of heterotopic syngeneic pancreaticoduodenal transplantation. Recipient animals were divided into two experimental groups: group Tx (n=7) received grafts without IPC, group Tx&IPC received grafts with IPC. Animals that had not undergone transplantation but whose pancreata had been exteriorized served as controls (n=5). All pancreatic grafts were preserved in University of Wisconsin solution for 6 h at 4 degrees C. IPC was induced by interruption of the arterial blood flow for 10 min followed by 10 min of reperfusion. One and two hours after reperfusion, graft microcirculation was assessed by means of intravital microscopy (IVM). Rats were immediately killed after the second measurement and DNA breaks of acinar cells were detected by in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate digoxigenin nick end-labelling (TUNEL) assay and gel electrophoresis (laddering). The apoptotic index (AI) was defined as the number of apoptotic cells per high-power field. Analysis of both groups of transplanted grafts showed a significant decrease in functional capillary density (FCD) and a significant increase in leukocyte sticking to postcapillary venules (LAV) at 1 h and 2 h of reperfusion, compared with animals that had not undergone transplantation ( P<0.01). In parallel, AI was significantly increased in transplanted grafts compared to the controls ( P<0.01). Grafts subjected to IPC showed no significant differences, neither for FCD nor LAV, at both time points if compared with grafts of group Tx. However, IPC resulted in a significant increase in AI ( P<0.05). We can conclude that IPC has no effect on pancreatic microcirculation but enhances acinar cell apoptosis in experimental pancreas transplantation. These results indicate that IPC might increase I/R injury after pancreatic cold ischemia.

Animals↗

PubMed2004

Dynamic intravital fluorescence microscopy--a novel method for the assessment of microvascular permeability in acute pancreatitis.

Edema formation is the first manifestation of acute pancreatitis. Microcirculatory derangements like leukocyte-endothelial cell interaction and perfusion failure result in enhancement of microvascular permeability to large molecules playing a pivotal role in the progression of the acutely altered pancreatic tissue. Due to the lack of suitable methods the crucial mechanisms of enhanced permeability in vivo are not very well investigated. Sprague-Dawley rats were randomly assigned to three groups: (a) sham operated animals with normal pancreas, (b) the pancreatitis group induced by 60 min temporary occlusion of the arterial supply followed by reperfusion and (c) the histamine group in which the pancreas was superfused with 10(-5)M histamine. The pharmacokinetics of tetramethylrhodamine-labelled BSA in the intravital microscopic images of a capillary network of the pancreas were densitometrically quantified over 20 min. From these data the effective microvascular permeability was calculated taking also into account morphology of microvessels, elimination rate of the tracer from the intravascular space and capillary microhematocrit. In addition macromolecular leakage of gold-labelled BSA was investigated by electron microscopy. Microvascular permeability was 0.10 +/- 0.02 x 10(-7) cm/s, 0.49 +/- 0.04 x 10(-7) cm/s and 1.21 +/- 0.29 x 10(-7) cm/s for control, ischemia and histamine group, respectively (P < 0.05 ischemia, histamine vs. control and ischemia vs. histamine). Electron microscopy revealed albumin extravasation in the last two groups. We established a technique allowing to quantify microvascular permeability in pancreatic tissue by dynamic intravital microscopy being independent of the investigator. This technique enabling accurate pathophysiologic characterisation in terms of edema formation can form the basis for evaluating in the future novel treatment strategies directed against acute pancreatitis.

Animals↗

PubMed2004

Brain death impairs pancreatic microcirculation.

Brain death (BD) influences the quality of donor grafts in transplantation. To evaluate the impact of BD on pancreas grafts, we investigated the influence of BD on the microcirculation and histology of the pancreas in a rat model of explosive BD. A group of Wistar rats (n=7), rendered brain dead by inflating an intracranially inserted Fogarty catheter was compared with controls (CO) using intravital epifluorescence-microscopy over 4 h after BD induction; functional capillary density (FCD), leukocyte adherence (AL) in post-capillary venules, histology and pancreatic enzymes were investigated. Four hours after BD, FCD decreased (333 +/- 11 vs. baseline 444 cm/cm2 +/- 5 SEM; p<0.01) and showed lower values than CO (388 +/- 9 p<0.01). In BD, AL was increased (628 cells/mm2 +/- 110 SEM vs. baseline 123 +/- 32, and vs. CO 180 +/- 33; p<0.001). BD caused increased histological damage (CO 1.6 score-points +/- 0.7 SD vs. BD 8.3 +/- 7.1; p<0.05). Amylase was higher in BD (p<0.05) but did not reach pathological values. We show for the first time that BD causes relevant changes in pancreatic microcirculation, histology and leukocyte endothelial interaction which might have a serious impact on the function of grafts. New strategies for preventing this damage are therefore highly desirable in order to improve the outcome of pancreas transplantation.

Amylases↗

PubMed2004

Recombinant human hemoglobin with reduced nitric oxide-scavenging capacity restores effectively pancreatic microcirculatory disorders in hemorrhagic shock.

BACKGROUND: Scavenging of nitric oxide by hemoglobin-based oxygen carriers could aggravate microcirculatory failure in splanchnic organs after hemorrhagic shock as a consequence of vasoconstrictive side effects. The aim of this study was to compare the effects of two recombinant human hemoglobin solutions, a second-generation product bearing reduced nitric oxide-scavenging properties (rHb2.0) due to site directed mutagenesis of the heme pocket and a first-generation recombinant hemoglobin (rHb1.1) with scavenging capacity similar to native hemoglobin, on the pancreatic microcirculation after hemorrhagic shock. METHODS: Twenty-eight pentobarbital-anesthetized rats were bled to a mean arterial pressure of 40 mmHg and maintained at this level for 1 h. Using an intravital microscope, the length of erythrocyte-perfused pancreatic capillaries per observation area (functional capillary density) were measured in animals resuscitated by volumes of hydroxyethyl starch, rHb1.1, or rHb2.0 equivalent to the shed blood volume. Animals without shock induction served as control. RESULTS: As compared with control (438 +/- 10 cm(-1)), animals treated with hydroxyethyl starch (315 +/- 44 cm(-1)) and rHb1.1 (288 +/- 67 cm(-1)) showed a significant reduction of functional capillary density after 2 h of resuscitation. rHb2.0 was able to restore functional capillary density (410 +/- 42 cm(-1)) and mean arterial pressure to baseline values. CONCLUSION: rHb2.0 was effectively able to restore pancreatic microcirculation after hemorrhagic shock. This may be related to the compound's effective lack of nitric oxide-scavenging properties. This hemoglobin solution or ones similar to it might be uniquely valuable for resuscitation from hemorrhagic shock.

Animals↗

PubMed2004

Expression of connexin26 in islets of Langerhans is associated with impaired glucose tolerance in patients with pancreatic adenocarcinoma.

OBJECTIVES: Impairment of glucose tolerance is one of the leading clinical presentations in patients with pancreatic carcinoma. The mechanism of disturbed glucose metabolism, however, is still under debate. Using microarray technology, key mechanisms of deregulated molecular functions of cancer cell-specific mRNAs and tumor-induced mRNAs in peritumorous tissue should be identified in pancreatic ductal adenocarcinoma (PDAC) by comparison to chronic pancreatitis and normal pancreas. METHODS: Forty-three mRNAs were abundant in tissue specimens of patients operated due to pancreatic carcinoma but absent or of low abundance in chronic pancreatitis and normal pancreas. One of these mRNAs encodes the gap junction protein connexin26, known as a tumor suppressor, which was 10.8- and 6.9-fold more abundant in pancreatic carcinoma than in normal pancreas and chronic pancreatitis, respectively. Quantitative RT-PCR was performed for connexin26, with mRNA being expressed 26.7- and 2.9-fold more than in normal pancreas (n = 6), in pancreatic carcinoma (n = 7), and chronic pancreatitis (n = 8), respectively. RESULTS: By immunohistochemistry, connexin26 was predominantly localized to the islets in the vicinity of the pancreatic carcinoma tissue. Control sections of tissue with chronic pancreatitis and normal pancreas show connexin26 expression in the islets as well. Interestingly, the level of mRNA abundance (fold over normal pancreas) in RT-PCR correlates (r = 0.62) with the 2h value of the pre-operative oral glucose tolerance test of these patients. CONCLUSION: Whether overexpressed connexin26 in pancreatic cancer is a cause of impaired glucose tolerance remains to be elucidated in further experimental studies.

Adenocarcinoma↗

PubMed2004

Effects of organ preservation, ischemia time and caspase inhibition on apoptosis and microcirculation in rat pancreas transplantation.

This study was undertaken to examine the impact of ischemia-reperfusion (I/R) injury on microcirculation and apoptosis in experimental pancreas transplantation. Pancreatic grafts were subjected to different preservation solutions and cold ischemia times (CITs): University of Wisconsin (UW), 6-h CITs (group U6); UW, 18-h CITs (group U18); normal saline, 6-h CITs (group S6); and normal saline, 6-h CITs with Z-Asp-2,6-dichlorobenzoyloxymethylketone (pan-caspase inhibitor; group S6 & CI). Nontransplanted animals served as controls. At 1- and 2-h reperfusion microcirculation was assessed by means of intravital microscopy. Apoptosis was detected by in situ nick end-labeling method (TUNEL) at 2-h reperfusion. Deterioration of microcirculation was lowest in group U6 and highest in groups S6 and S6 & CI compared with controls. The apoptotic index (cells per high power fields) of groups U6, U18 and S6 correlated well with functional capillary density (r=- 0,70, p < 0.0001) and leucocyte sticking (r= 0,69, p < 0.0001) at 1-h reperfusion. Caspase inhibition had no impact on microcirculation but significantly reduced AI compared with group S6 (p < 0.001). These data suggest that pancreatic I/R injury-induced apoptotic cell death well predicts the extent of [corrected] microcirculatory impairment. Caspase inhibition might be a promising strategy in reducing I/R injury in pancreas transplantation.

Animals↗

PubMed2003

Postoperative oral glucose tolerance and stimulated insulin secretion: a predictor of endocrine graft function more than 10 years after pancreas-kidney transplantation.

BACKGROUND: After pancreas transplantation, endocrine function is determined by the insulin secretory capacity of the transplanted pancreas. The authors evaluated the predictive value of postoperative oral glucose tolerance test (OGTT) and stimulated insulin secretion on long-term endocrine function. METHODS: Forty-one patients after pancreas-kidney transplantation with systemic venous drainage were studied. Patients were categorized to have normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) (World Health Organization criteria: NGT, <7.8 mM; IGT, 7.8-11.1 mM 120 min after glucose intake) and high or low total insulin secretion. Mean follow-up of graft function and patient outcome was 10.2+/-0.5 years after OGTT. RESULTS: Patients with IGT had grafts with a longer ischemia time and a significantly worse urine amylase excretion as compared with patients with NGT. Using Kaplan-Meier survival analysis, patients with NGT had better long-term pancreatic function as compared with IGT in the follow-up after performing the first OGTT (mean, 10.9+/-0.2 vs. 8.8+/-0.9 years of graft function; P=0.02), but there was no difference in patient survival and kidney graft function. Also, high insulin secretion predicted significantly longer pancreas graft function as compared with low insulin secretion (P=0.04). CONCLUSIONS: Although IGT does not lead to poorer long-term patient survival and kidney graft function, it does predict compromised long-term endocrine function of the transplanted pancreas. Therefore, postoperative OGTT are useful tools for identification of patients at risk of long-term endocrine graft failure after pancreas transplantation.

Adult↗

PubMed2003

Endotoxin preconditioning in pancreatic ischemia/reperfusion injury.

OBJECTIVES: Prospective organ donors are exposed to various stress types. The effect of endotoxin pretreatment (ETX) on pancreatic ischemia/reperfusion injury (IRI) is unclear. We investigated, using a rat model of pancreatic IRI of an in situ isolated pancreatic tail segment, the effect of ETX on postischemic microcirculation and organ damage. METHODS: Twenty-four hours before pancreatic dissection, either intraperitoneal application of ETX (1 mg/kg in 0.9% NaCl) or saline only (control) was performed. Two-hour normothermic ischemia of the pancreatic tail was induced by clamping the splenic vessels and was followed by a reperfusion period of 2 hours. Microcirculatory parameters were measured by intravital epifluorescence microscopy [functional capillary density (FCD), adherent leukocytes (ALs), and histology]. The presented data represent the mean +/- SEM/SD as appropriate. RESULTS: ETX pretreatment caused a significantly greater decrease in FCD (497 +/- 6 cm/cm2 baseline versus 326 +/- 15 cm/cm2 2 hours of reperfusion) compared with controls (498 +/- 8 versus 258 +/- 15 cm/cm2) 2 hours after reperfusion (P < 0.01). Two hours after reperfusion, ALs were significantly decreased in ETX animals compared with controls (ETX: 141 +/- 37 versus 273 +/- 36 cells/mm2, P < 0.05). Histologic damage was less in ETX (6.4 score points +/- 0.32 versus 8.8 +/- 0.33 control, P < 0.05). CONCLUSION: ETX preconditioning decreases microcirculatory deterioration caused by IRI by means of less loss of nutritive tissue perfusion, decrease in ALs, and less histologic damage. This indicates a protective effect of ETX preconditioning in pancreatic IRI.

Animals↗