[Discolouration of Upper Lid Skin - Prurigo nodularis]. / Hautverfärbung am Oberlid ­ Prurigo nodularis.

An abnormal change in skin colour is designated as discolouration of the skin. A 73-year-old male patient with circumscribed discolouration of the upper lid margin near the lacrimal pathway is presented. Slit lamp biomicroscopy showed no other signs of pathomorphological change. An excisional biopsy was performed. The whole abnormal area was removed. The oculoplastic procedure was the surest way to establish a definite diagnosis of Prurigo nodularis.

Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans.

Intrahepatic cholangiocarcinoma (ICC) is a rare yet deadly malignancy with limited treatment options. Activation of the Notch signalling cascade has been implicated in cholangiocarcinogenesis. However, while several studies focused on the Notch receptors required for ICC development, little is known about the upstream inducers responsible for their activation. Here, we show that the Jagged 1 (Jag1) ligand is almost ubiquitously upregulated in human ICC samples when compared with corresponding non-tumorous counterparts. Furthermore, we found that while overexpression of Jag1 alone does not lead to liver tumour development, overexpression of Jag1 synergizes with activated AKT signalling to promote liver carcinogenesis in AKT/Jag1 mice. Histologically, tumours consisted exclusively of ICC, with hepatocellular tumours not occurring in AKT/Jag1 mice. Furthermore, tumours from AKT/Jag1 mice exhibited extensive desmoplastic reaction, an important feature of human ICC. At the molecular level, we found that both AKT/mTOR and Notch cascades are activated in AKT/Jag1 ICC tissues, and that the Notch signalling is necessary for ICC development in AKT/Jag1 mice. In human ICC cell lines, silencing of Jag1 via specific small interfering RNA reduces proliferation and increases apoptosis. Finally, combined inhibition of AKT and Notch pathways is highly detrimental for the in vitro growth of ICC cell lines. In summary, our study demonstrates that Jag1 is an important upstream inducer of the Notch signalling in human and mouse ICC. Targeting Jag1 might represent a novel therapeutic strategy for the treatment of this deadly disease.

[Molecular and metabolic changes in human clear cell liver foci]. / Molekulare und metabolische Veränderungen in humanen klarzelligen Leberherden.

Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype are evident both in human hepatocellular carcinoma and in the rat model of insulin-induced hepatocarcinogenesis in the earliest preneoplastic lesions, i.e. clear cell foci (CCF) of altered hepatocytes. These CCFs have also been described in the human liver but characterization of molecular and metabolic changes are still pending. In this study, human sporadic CCFs were investigated in a collection of human non-cirrhotic liver specimens using histology, histochemistry, immunohistochemistry, electron microscopy and molecular pathological analysis. Human CCFs occurred in approximately 33 % of non-cirrhotic livers and stored masses of glycogen in the cytoplasm, largely due to reduced activity of glucose-6-phosphatase. Hepatocytes revealed an upregulation of the AKT/mTOR and the Ras/MAPK pathways, the insulin receptor, glucose transporters and enzymes of glycolysis and de novo lipogenesis. Proliferative activity was 2-fold higher than in extrafocal tissue. The CCFs of altered hepatocytes are metabolically and proliferatively active lesions even in humans. They resemble the well-known preneoplastic lesions from experimental models in terms of morphology, glycogen storage, overexpression of protooncogenic signaling pathways and activation of the lipogenic phenotype, which are also known in human hepatocellular carcinoma. This suggests that hepatic CCFs also represent very early lesions of hepatocarcinogenesis in humans.

[Autoimmune pancreatitis]. / Autoimmunpankreatitis.

Autoimmune pancreatitis is a relatively rare form of chronic pancreatitis which is characterized by a lymphoplasmatic infiltrate with a storiform fibrosis and often goes along with painless jaundice and discrete discomfort of the upper abdomen. Clinically we distinguish between two subtypes, which differ in terms of their histology, clinical picture and prognosis. Type 1 autoimmune pancreatitis is the pancreatic manifestation of the IgG4-associated syndrome which also involves other organs. About one third of the patients can only be diagnosed after either histological prove or a successful steroid trail. Type 2 is IgG4-negative with the histological picture of an idiopathic duct centric pancreatitis and is to higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made using biopsy. Usually both forms show response to steroid treatment, but in type 1 up to 50 % of the patients might develop a relapse. The biggest challenge and most important differential diagnosis remains the discrimination of AIP from pancreatic cancer, because also AIP can cause mass of the pancreatic head, lymphadenopathy and ductal obstruction. This article summarizes recent advances on epidemiology, clinical presentation, diagnostic strategy, therapy and differential diagnosis in this relatively unknown disease.

Effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on rat vascular smooth muscle in vitro--the role of the endothelium.

Hypotension is a frequent side effect of the antidepressant treatment. It is controversial whether this effect is attributable to interactions within the central nervous or the cardiovascular system. We examined often used antidepressants for their vasoactive properties in vitro in rat aortal rings with and without endothelium. The influence of pre-incubation with the antidepressants (0.5 µM) on adrenergic elicited smooth muscle contraction and the effects of cumulative concentrations (0.05 µM-500 µM) of the antidepressants on isometric tension were measured. In addition, conceivable modulation of the NO-cGMP, adrenergic and potassium channel pathways were examined. Amitriptyline and fluoxetine inhibited, whereas tranylcypromine enhanced adrenergic elicited responses of smooth muscle contraction. The antidepressants amitriptyline, fluoxetine and tranylcypromine showed, to a different extent, vasorelaxing properties in the preparations pre-contracted with phenylephrine 0.1 µM; the pEC50, (means and S.E.M.) in descending order of potency: amitriptyline 6.98 (0.13), fluoxetine 6.11 (0.05), tranylcypromine 5.33 (0.05) (n=8 each, preparations with endothelium); or after pre-contraction with KCl 20 mM: fluoxetine 6.00 (0.06), tranylcypromine 4.99 (0.30), amitriptyline, 4.89 (0.11), (n=7 each, preparations with endothelium). Venlafaxine did not relax the aortal rings and even lead to further contraction of the endothelium intact preparations. The observed effects were partially endothelium dependent via activation of the NO-cGMP pathway and some probably mediated through K+ channel activation. Amitriptyline, fluoxetine and tranylcypromine relax rat aorta in vitro. They partially delay vascular smooth muscle reactions to adrenergic agonists and can lead to sustained hypotension episodes despite administration of sympathomimetic drugs.