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D Uhlmann

Publications and source records attributed to D Uhlmann.

At least 19 recordsLinked to original sources
PubMed2007

Sirolimus improves early microcirculation, but impairs regeneration after pancreatic ischemia-reperfusion injury.

Ischemia and reperfusion injury remains a relevant problem in clinical pancreas transplantation. We investigated the effect of sirolimus (SRL) in a rodent model of 90-min warm pancreatic ischemia. Four groups were studied: (1) sham surgery and vehicle; (2) sham surgery and SRL; (3) warm ischemia and vehicle; (4) warm ischemia and SRL. SRL (1.5 mg/kg/day) and vehicle were administered intraperitoneally for 3 days prior to surgery until the animals were killed. Microcirculation was assessed immediately after reperfusion by means of intravital fluorescence microscopy. Histopathological injury, apoptosis, proliferation and biochemical parameters were analyzed at 2 h, 1 day and 5 days after surgery. Ninety minutes after ischemia, intravital microscopy revealed an improved functional capillary density (p < 0.05) and reduction of adherent leucocytes (p < 0.01) and platelets (p < 0.05) in the SRL-treated group compared to the vehicle-treated controls. In contrast, on day 5 after ischemia, the pancreatic tissue of SRL-treated animals showed a higher grade of histological injury (p < 0.05) and higher rate of apoptotic cells (p < 0.05) than the vehicle controls. In summary, our data indicate that administration of SRL improves microcirculation at a very early stage, but results in an impairment of the recovery phase after pancreatic ischemia-reperfusion injury.

Animals↗
PubMed2004

[The influence of normobaric hyperoxia on hepatic oxygenation--experience with an animal model].

We investigated the effect of a ventilation with an FiO2 of 1.0 on arterial and hepatic venous oxygenation in 23 Göttingen minipigs. Under balanced anaesthesia (isoflurane/fentanyl), a fibreoptic catheter was placed into a hepatic vein. The correct position of the tip of the catheter was controlled manually after laparotomy. After measurement of baseline values (arterial and hepatic blood gases, ShvO2), in 13 minipigs normoventilation with an FiO2 of 1.0 was performed for 15 minutes. Thereafter, ventilation was continued with an FiO2 of 0.4. In the control group (n = 10), the animals were oxygenated with an FiO2 of 0.4 permanently. The changes due to hyperoxia were measured in hepatic venous oxygen saturation (ShvbgaO2: from 81.2 +/- 1.43% to 87.5 +/- 1.77%, ShvoximO2: from 82.6 +/- 1.14% to 90.5 +/- 0.90%), arterial (from 217.5 +/- 5.0 mmHg to 467.2 +/- 22.0 mmHg) and hepatic venous (from 51.8 +/- 2.0 mmHg) oxygen partial pressure. We found a correlation between hepatic venous oxygen partial pressure und ShvbgaO2 in the blood (r = 0.84, p < 0.001) and between ShvO2 (ShvbgaO2/ShvoximO2), which was either measured directly in the blood or by a fibreoptic catheter (r = 0.6, p < 0.001). Whereas the increase in ShvO2 during hyperoxia may be a result of increased arterial supply, the decrease in ShvO2 after the end of hyperoxia below baseline values needs further investigations. The continuous fibreoptic measurement of ShvoximO2, also under hyperoxic conditions is a valuable parameter for the monitoring of hepatic venous oxygenation.

Animals↗
PubMed2003

Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma.

BACKGROUND: The Raf/MEK/ERK (mitogen activated protein kinase-MAPK) signal transduction cascade is an important mediator of a number of cellular fates, including growth, proliferation, and survival. The BRAF gene, one of the human isoforms of RAF, is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. AIMS: The aim of this study was to elucidate a possible function of BRAF in liver tumours. METHODS: Mutations of BRAF and KRAS were evaluated in 25 hepatocellular carcinomas (HCC) and in 69 cholangiocarcinomas (CC) by direct DNA sequencing analyses after microdissection. The presence of active intermediates of the MAPK pathway was assessed immunohistochemically. The results obtained were correlated with histopathological variables and patient survival. RESULTS: Activating BRAF missense mutations were identified in 15/69 CC (22%) and in one case of tumour surrounding liver. KRAS mutations were found in 31 of 69 (45%) CC examined and in two cases of tumour surrounding non-neoplastic liver tissue. In HCC, neither BRAF nor KRAS mutations were detected. All 31 CC with KRAS mutations had an intact BRAF gene. We failed to observe a correlation between BRAF or KRAS mutations and histopathological factors or prognosis of patients. CONCLUSIONS: Our data indicate that BRAF gene mutations are a relatively common event in CC but not in HCC. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway, either by RAS or BRAF mutation, was detected in approximately 62% of all CC and is therefore one of the most frequent defects in cholangiocellular carcinogenesis.

Base Sequence↗
PubMed2001

Protective role of an endothelin-converting enzyme inhibitor (FR901533) in hepatic ischemia/reperfusion injury.

INTRODUCTION: There is evidence that endothelin (ET) contributes to disturbances of the hepatic microcirculation after warm ischemia/reperfusion (I/R) by causing vasoconstriction and by enhancing leukocyte endothelium interactions. The aim of this study was to investigate a possible protective role of the endothelin converting enzyme (ECE) inhibitor FR901533 in this setting. METHODS: In an in vivo model (42 Wistar rats), hepatic ischemia was induced for 30 min by Pringle's maneuver. Sham operated (I), untreated ischemic (II), and treatment (III) groups with FR901533 (1 mg/kg bw iv) were investigated. The effect of FR901533 in I/R was assessed by in vivo microscopy (30-90 min after reperfusion), measurement of local tissue pO2 (30 and 60 min after reperfusion), and determination of AST/ALT levels (2 h, 6 h, and 2, 6, and 14 days after reperfusion). RESULTS: In the untreated ischemic group (II) sinusoidal constriction to 76.3 +/- 4.2% of basic diameters was observed, leading to significant decreases in perfusion rate (82.3 +/- 3.6% of sham group) and in liver tissue pO(2) (43.5 +/- 3.2% of sham group) (P < 0.05). In addition, we found an increased percentage of stagnant leukocytes in sinusoids (138.3 +/- 9.8) and sticking leukocytes in postsinusoidal venules (155.2 +/- 3.3% of sham group) (P < 0.05). Hepatocellular damage (AST/ALT increase to 430.6 +/- 47.7 U/L/200.2 +/- 23.8 U/L, pre: 27.4 +/- 2.7 U/L/28.1 +/- 2.7 U/L) was detected 6 h after reperfusion (P < 0.05). Administration of the ECE inhibitor before ischemia significantly reduced I/R injury. Sinusoidal diameters were maintained (102.2 +/- 1.7%), while perfusion rate (93.1 +/- 1.8%) and tissue pO2 (105.3 +/- 2.7%) increased significantly (P < 0.05). Hepatocellular damage was decreased (AST/ALT levels after 6 h of reperfusion: 166.6 +/- 26.3 U/L/132.4 +/- 22.5 U/L, P < 0.05) and leukocyte sticking and rolling were significantly reduced (P < 0.05). CONCLUSION: Our results provide evidence that the new therapeutic approach with an ECE inhibitor is effective in reducing hepatic I/R injury.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

p16INK4A-alterations in primary angiosarcoma of the liver.

BACKGROUND/AIMS: Alterations in the p16 (CDKN2/MTS-1/INK4A) gene have been implicated in the tumorigenesis of different human cancers. Recent evidence shows that transcriptional silencing as a consequence of hypermethylation of CpG islands is the predominant mechanism of p16INK4a gene inactivation in malignant epithelial tumors. This study was performed to determine whether alterations of p16 are involved in the development of angiosarcoma of the liver. METHODS: The status of p16 was evaluated in 17 angiosarcomas of the liver by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. The results obtained were correlated with histopathological variables and with patient survival. RESULTS: Hypermethylation of the 5' CpG island of the p16 gene was found in 12 out of 17 (71%) angiosarcomas examined. Homozygous deletion at the p16 region was present in one case (6%), and loss of heterozygosity was present in two cases (12%). We failed to detect p16 gene missense mutations. The status of p16 correlated with neither histopathological factors nor with the prognosis of the patients with angiosarcomas. CONCLUSIONS: These data suggest that inactivation of the p16 gene is a frequent event in angiosarcomas of the liver. The most common somatic alteration is promotor methylation of the p16 gene. We failed to establish p16 as independent prognostic factors in these tumors.

Aged↗
PubMed2001

[Surgery for complications of chronic pancreatitis].

At least 50 % of all patients with chronic pancreatitis require surgical treatment in the course of their disease. Indications for surgery are intractable pain, intra- and extrapancreatic complications and the suspicion of a carcinoma. The basic principles of surgery are resection and drainage. The choice of the surgical procedure depends on the morphological expression and the localization of the pathological changes. Regarding resections in the head-area, previous studies demonstrated uniformly the superiority of the duodenum-preserving pancreas head resection (DPPHR) compared to the Kausch-Whipple operation with and without maintenance of the pylorus. Drainage procedures (pain recurrence in 20-40 % in the long-term course) and left pancreatic resections (de-novo diabetes mellitus in up to 45 %) should be considered critically. Between May 1994 and November 2000 117 patients underwent surgical therapy for complications of chronic pancreatitis at our institution. Resections were performed in 68 % of the patients and drainage procedures in 20 %. There was no mortality. Over the years the proportion of the DPPHR increased in comparison to the Kausch-Whipple procedure and the number of the drainage operations decreased continuously. The DPPHR was significantly superior to the Kausch-Whipple procedure with regard to the glucose metabolism and the quality-of-life. In the spectrum of surgical procedures in chronic pancreatitis, the DPPHR represents a modern, organ-preserving procedure for patients with complications in the pancreas head.

Adolescent↗
PubMed2001

Importance of microcirculatory disturbances in the pathogenesis of pancreatitis.

Pancreatic microvascular control is a complex physiological process which is incompletely understood. Blood flow in the pancreas is altered by a large number of endogenous and exogenous factors in the context of acute and chronic pancreatitis. The frequency of progression from acute pancreatitis to a chronic form is a controversial question. In acute pancreatitis reductions in blood flow and alterations of microvascular integrity resulting in impaired tissue oxygenation play an important part in the progression and possibly the initiation of the disease. Endothelin and nitric oxide are believed to be two of the most effective vasoactive mediators. The beneficial effect of therapeutic strategies affecting vasoactive mediators is confirmed in experimental studies. Chronic disease is associated with decreased pancreatic blood flow and histological changes in the vasculature in both patients and animal models. Further studies are needed to clarify whether ischemia in chronic pancreatitis is more important in perpetuating the disease or as primary cause of the inflammatory processes.

Acute Disease↗
PubMed2001

Pharmacological regulation of postischemic sinusoidal diameters in rats--a new approach for reducing hepatic ischemia/reperfusion injury.

UNLABELLED: Ischemia leads to profound endothelin-related constriction of the hepatic microcirculation with resulting disturbances in blood and oxygen supply. The aim of the study was to modulate hepatic microvascular diameters by blocking endothelin receptors with bosentan, and also to find the best possible vessel width (as produced by bosentan) for minimizing ischemia/reperfusion injury. METHODS: In an in vivo rat model hepatic ischemia was induced for 30 minutes by crossclamping the hepatoduodenal ligament. The endothelin receptor antagonist (ERA) bosentan was administered before ischemia in stepwise dosages of 0.1, 1.0 and 10 mg/kg bw i.v. and 10 mg/kg bw intraportally (i.p.). Vasoactive effect was assessed by in vivo microscopy. The influence on hepatic oxygen supply and hepatocellular function was evaluated by measuring local tissue pO(2) and AST levels. RESULTS: Because of ischemia sinusoidal diameters were reduced to 76.3 +/- 7.4% compared with values found in sham-operated animals. After administration of 0.1 mg/kg ERA (bosentan) the sinusoids remained constricted (89.7 +/- 9.9%). Blocking endothelin receptors with 1 mg/kg bosentan avoided sinusoidal constriction (99.0 +/- 8.8%, p<0.05) and led to the most effective reduction of AST level peak after 6 h of reperfusion (244.0 +/- 34.2 U/l vs 422.9 +/- 163.3 U/l in untreated ischemia). 10 mg/kg i.v. caused an increase in sinusoidal diameter to 109.1 +/- 6.4% and 10 mg/kg intraportally to 136.8 +/- 19.3% and even an increase in AST levels (618.9 +/- 209.3 U/l). Hepatic ischemia led to a significant decrease of local tissue pO(2) after reperfusion (9.4 +/- 1.2 mm Hg; p<0.05 vs sham: 16.8 +/- 1.8 mm Hg). The greatest improvement in postischemic oxygen supply was found in the 1.0 mg/kg group (12.9 +/- 1.0 mm Hg; p< 0.05 vs ischemia). Venular diameter changed almost to the same extent as sinusoidal diameter. Perfusion rate was significantly increased and sticking of leukocytes in sinusoids and venules was reduced after doses of 1 and 10 mg/kg bw bosentan i.v. (p<0.05). IMPLICATIONS: In this model we were able to regulate the diameters of sinusoids and postsinusoidal venules incrementally. We conclude that the avoidance of constriction, without excessive vasodilatation gives increased perfusion rates with improved hepatic oxygen supply and hepatocellular function.

Animals↗
PubMed2000

Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma.

Reduced expression of the cyclin-dependent kinase inhibitor p27 has previously been correlated with fatal clinical outcome in some tumors, including gastric, breast, and prostate cancers. For hepatocellular carcinoma, the findings are equivocal. In situ hybridization and immunohistochemistry were performed on a series of 203 curatively (R0) resected hepatocellular carcinomas and in corresponding non-cancerous liver tissue to detect p27. Patients receiving liver transplantation were excluded. The results were correlated with histopathological stage according to the UICC system, Edmondson grade, several other histopathological factors of possible prognostic significance, and finally patient survival. Whereas p27 mRNA was expressed homogeneously in all carcinomas examined, the p27 protein was found in various amounts. The labeling index of p27 protein was significantly lower in advanced stages of the disease (P < 0.001, chi(2) = 28.1). We observed decreased p27 protein in higher pT categories (P < 0.001, chi(2) = 24.7) and in multiple tumor nodules (P < 0.001, chi(2) = 9.3). Multivariate Cox survival analysis identified age, co-existing cirrhosis, and Edmondson grade as independent prognostic factors. We conclude that evaluation of p27 in hepatocellular carcinoma is useful to predict stage of disease and may have clinical significance, e.g., in predicting optimal therapeutic regimes.

Adult↗