Ingo Theuerkauf

Adenoviral expression of a transforming growth factor-β1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats

BackgroundTransforming growth factor-β (TGF-β) is a key mediator in establishing liver fibrosis. Therefore, TGF-β as a causative agent may serve as a primary target for antifibrotic gene therapy approaches. We have previously shown that the adenoviral delivery of a transgene constitutively expressing a TGF-β1 antisense mRNA blocks TGF-β synthesis in culture-activated hepatic stellate cells and effectively abolishes ongoing fibrogenesis in vitro.MethodsLigature of the common bile duct was used to induce liver fibrosis in rats. The effect of the TGF-β1 antisense on fibrogenesis was analyzed in this model of liver injury.ResultsIn the present study, we demonstrate that the adenoviral vector directs the synthesis of mRNA quantities that are approximately 8000-fold more abundant than endogenous TGF-β1 mRNA. In experimentally injured rat livers induced by ligature of the common bile duct, a model for persistent fibrogenesis and cirrhosis, administration of the adenoviral vector abrogates TGF-β-enhanced production of collagen and α-smooth muscle actin. Furthermore, the number of cells positive for α-smooth muscle actin resulting from active recruitment of activated hepatic stellate cells around the bile ductular structures was significantly reduced in animals after application of Ad5-CMV-AS-TGF-β1. However, the observed elevated serum levels of aspartate aminotransferase, alanine aminotransferase, and bilirubin induced in this obstructive liver injury model were not significantly altered in the presence of the TGF-β antagonist.ConclusionTaken together, our data provides in vivo evidence that the delivery of TGF-β1 antisense mRNA specifically abolishes the diverse effects of direct TGF-β function in ongoing liver fibrogenesis. Therefore, we conclude that the expressed transgene is therapeutically useful for inhibition of TGF-β effects in diverse applications, ranging from clarification of TGF-β function in the course of liver injury to the development of novel gene therapeutic approaches.

Immunohistochemical patterns of human liver sinusoids under different conditions of pathologic perfusion

Abstract. This study reports the effects of altered hepatic perfusion on the sinusoidal bed and the phenotypic characteristics of sinusoidal endothelial cells (SECs). Sinusoids were studied by the application of endothelial cell markers (CD31, CD34, CD105, and ATZ 11) in lesions with localized increased perfusion (liver cell adenoma, focal nodular hyperplasia, and macroregenerative nodule), in chronic congestion, in decreased portovenous inflow (portal vein thrombosis), and in decreased arteriohepatic perfusion (obliterative arteriopathy in chronic allograft rejection). SECs react in a sensitive and uniform way to all investigated conditions of different pathologic liver perfusion: expression of CD31, CD34, and ATZ 11 by SEC is found in inflow areas, CD105-positive SECs are found at the end of the sinusoidal blood stream. This blood flow-orientated phenotypic shift of SECs was accompanied by a perisinusoidal accumulation of activated hepatic stellate cells and collagen IV. These findings are helpful in liver biopsies and provide new insights into the angioarchitecture of benign nodular lesions.

Infarction and laceration of liver parenchyma caused by wedged CO2 venography before TIPS insertion

We describe the fatal outcome of an elective TIPS procedure performed in a 43-year-old man with alcoholic cirrhosis. Wedged hepatic venography with CO2 was the reason for infarction and laceration of liver parenchyma resulting in a subcapsular hematoma and subsequent intra-abdominal bleeding. This is the first report of this complication after the use of CO2 in a cirrhotic patient.

The three-dimensional ultrasound evaluation of the rotator cuff--an experimental study.

OBJECTIVE An accurate sonographic diagnosis of rotator cuff lesions significantly depends on image quality and on the experience of the operator. The present study was performed to determine whether the use of three dimensional (3D) sonography further increases the diagnostic yield of ultrasound. METHODS In an experimental study 22 artificial rotator cuff lesions (seven full thickness and 15 partial thickness tears) of cadaveric shoulder joints were evaluated by ultrasound with two and three dimensional imaging in a water basin. RESULTS With 3D ultrasound, rotator cuff lesions were more often correctly diagnosed (sensitivity of 77%) than with conventional 2D sonography (sensitivity of 64%). Specificity was 85 and 69%, respectively. In partial thickness tears in particular, 3D imaging was the superior method reaching a sensitivity and specificity of 73 and 77%, respectively, compared to 53 and 61%, respectively, with 2D ultrasound. With 2D and 3D ultrasound eight and 11 out of 13 tendons, respectively, were correctly diagnosed as intact confirmed by histopathological examination. CONCLUSION Although the results of an experimental study may not reflect the clinical situation, 3D ultrasound appears to facilitate diagnosis of partial thickness rotator cuff tears.

Segmental hepatic vein thrombosis associated with heparin-induced thrombocytopenia II

Abstract We report the case of a 55-year-old man who developed heparin-induced thrombocytopenia II after a vertebral fracture. Autopsy revealed segmental hepatic vein thrombosis of the right lobe with subacute congestion and an activation of hepatic stellate cells. This case shows that heparin-induced thrombocytopenia II is a possible cause of the Budd-Chiari syndrome.

Malignant Mediastinal Germ Cell Tumor with Pure Hepatoid Differentiation

We describe a germ cell tumor of anterior mediastinal origin, with pure hepatoid differentiation and elevated serum AFP in a 41-year-old man. This is the first report of such a neoplasm analyzed by conventional stains and immunohistochemistry. Hepatocellular differentiation was proved by immunoreactivity with HepPar-1 and alpha-fetoproein (AFP), membranous expression of carcinoembryonic antigen (CEA-poly) in a canalicuar pattern, and focal expression of cytokeratin 19 in abortive ductular structures. Our investigation shows that mediastinal germ cell tumors with hepatoid components typically arise in middle-aged men; they are of pure hepatoid differentiation, as demonstrated here, or exclusively associated with yolk sac structures.

Massiver Pulmonalkapillarenverschluss durch MikrothrombenUnerwartete Ursache eines tödlichen Rechtsherzversagens während Lebertransplantation

ZusammenfassungWir berichten über einen 46-jährigen Patienten, der intraoperativ während einer zunächst komplikationslosen orthotopen Lebertransplantation ein kardiales Pumpversagen entwickelt hat. Die Reanimation blieb erfolglos. Die Autopsie ergab als Todesursache ein Rechtsherzversagen bei einem Verschluss peripherster Pulmonalarterien und -kapillaren durch Mikrothromben. Andere Organe waren frei von Mikrothromben. Die Ursache bzw. der genaue Ort der Thrombenentstehung ist unklar. Prinzipiell sind eine embolische Verschleppung von intrahepatisch entstandenen Mikrothromben in die Lunge, eine Ausbildung von Mikrothromben auf dem Weg zur Lunge oder in der Lungenstrombahn selbst zu diskutieren. Die beschriebene Komplikation ist unserer Erfahrung nach sehr selten, das dazu prädisponierende Risikoprofil ist unbekannt.AbstractWe report the case of a 46-year old man who developed an unexpected fatal cardiac failure during liver transplantation. Attempts at resuscitation were unsuccessful. At necropsy the lungs showed numerous microthrombi occluding small lung vessels and pulmonary capillaries. Thrombi were not found in other organs. The source of this extensive thrombus formation is not known. The thrombi could have been developed within the liver, the venous blood stream between liver and lungs or the pulmonary capillaries. In our experience, this complication is very rare, and a risk profile is not known.

Massive pulmonary capillary occlusion by microthrombi. Unexpected cause of fatal right heart failure during liver transplantation

ZusammenfassungWir berichten über einen 46-jährigen Patienten, der intraoperativ während einer zunächst komplikationslosen orthotopen Lebertransplantation ein kardiales Pumpversagen entwickelt hat. Die Reanimation blieb erfolglos. Die Autopsie ergab als Todesursache ein Rechtsherzversagen bei einem Verschluss peripherster Pulmonalarterien und -kapillaren durch Mikrothromben. Andere Organe waren frei von Mikrothromben. Die Ursache bzw. der genaue Ort der Thrombenentstehung ist unklar. Prinzipiell sind eine embolische Verschleppung von intrahepatisch entstandenen Mikrothromben in die Lunge, eine Ausbildung von Mikrothromben auf dem Weg zur Lunge oder in der Lungenstrombahn selbst zu diskutieren. Die beschriebene Komplikation ist unserer Erfahrung nach sehr selten, das dazu prädisponierende Risikoprofil ist unbekannt.AbstractWe report the case of a 46-year old man who developed an unexpected fatal cardiac failure during liver transplantation. Attempts at resuscitation were unsuccessful. At necropsy the lungs showed numerous microthrombi occluding small lung vessels and pulmonary capillaries. Thrombi were not found in other organs. The source of this extensive thrombus formation is not known. The thrombi could have been developed within the liver, the venous blood stream between liver and lungs or the pulmonary capillaries. In our experience, this complication is very rare, and a risk profile is not known.

Perforation eines mucocelenartig transformierten Hartmannstumpfs

Abstract. We report an unusual complication in a 53-year-old woman following ileostomy for Crohns disease 22 years previously. A stenosis of the distal colonic segment was the reason for the formation and subsequent rupture of a huge colonic mucocele. To our knowledge, this is the first report of a ruptured mucocele of colonic origin after ileostomy.Zusammenfassung. Wir berichten über eine 53 jährige Patientin, bei der 22 Jahre nach Anlage eines Ileostomas wegen eines Morbus Crohn eine Stenose im distalen Colonsegment (Hartmannstumpf) zu einer mucocelenartigen Transformation und nachfolgenden Ruptur geführt hat. Über die Ruptur eines stillgelegten Colonabschnitts nach Anlage eines Ileostomas wurde bisher offenbar noch nicht berichtet.

Massiver Pulmonalkapillarenverschluss durch Mikrothromben Unerwartete Ursache eines tödlichen Rechtsherzversagens während Lebertransplantation: Unerwartete Ursache eines tödlichen Rechtsherzversagens während Lebertransplantation

ZusammenfassungWir berichten über einen 46-jährigen Patienten, der intraoperativ während einer zunächst komplikationslosen orthotopen Lebertransplantation ein kardiales Pumpversagen entwickelt hat. Die Reanimation blieb erfolglos. Die Autopsie ergab als Todesursache ein Rechtsherzversagen bei einem Verschluss peripherster Pulmonalarterien und -kapillaren durch Mikrothromben. Andere Organe waren frei von Mikrothromben. Die Ursache bzw. der genaue Ort der Thrombenentstehung ist unklar. Prinzipiell sind eine embolische Verschleppung von intrahepatisch entstandenen Mikrothromben in die Lunge, eine Ausbildung von Mikrothromben auf dem Weg zur Lunge oder in der Lungenstrombahn selbst zu diskutieren. Die beschriebene Komplikation ist unserer Erfahrung nach sehr selten, das dazu prädisponierende Risikoprofil ist unbekannt.AbstractWe report the case of a 46-year old man who developed an unexpected fatal cardiac failure during liver transplantation. Attempts at resuscitation were unsuccessful. At necropsy the lungs showed numerous microthrombi occluding small lung vessels and pulmonary capillaries. Thrombi were not found in other organs. The source of this extensive thrombus formation is not known. The thrombi could have been developed within the liver, the venous blood stream between liver and lungs or the pulmonary capillaries. In our experience, this complication is very rare, and a risk profile is not known.