The recently identified claudins are dominant components of tight junctions, responsible for cell adhesion, polarity and paracellular permeability. Certain claudins have been shown to have relevance in tumor development, with some of them, especially claudin-4, even suggested as future therapeutic target. The aim of the present study was to analyze the expression of claudin-4 in the biliary tree, biliary tract cancers and hepatocellular carcinomas. A total of 107 cases were studied: 53 biliary tract cancers, 50 hepatocellular carcinomas, 10 normal liver and 10 normal extrahepatic biliary duct samples. Immunohistochemical analysis was performed on conventional specimens and on tissue microarrays as well. Claudin-4 was further investigated by Western blot analysis and real-time RT-PCR. Intense membranous immunolabeling was found for claudin-4 in all biliary tract cancers unrelated to the primary site of origin, namely intrahepatic, extrahepatic or gallbladder cancers. Normal biliary epithelium showed weak positivity for claudin-4. In contrast, normal hepatocytes and tumor cells of hepatocellular carcinomas did not express claudin-4. The results of Western immunoblot analysis and real-time RT-PCR were in correlation with the immunohistochemical findings. Cytokeratins, as CK7 (92%) and CK19 (83%) were mostly positive in biliary tract cancers, however, one-third of hepatocellular carcinomas also expressed CK7 (34%). HSA antibody (HepPar1) reacted with the majority of hepatocellular carcinomas (86%), while being positive in a low percentage of the biliary tract cancers (8%). In conclusion, this is the first report of a significantly increased claudin-4 expression in biliary tract cancers, which represents a novel feature of tumors of biliary tract origin. Claudin-4 expression seems to be a useful marker in differentiating biliary tract cancers from hepatocellular carcinomas and could well become a potential diagnostic tool.

Abstract-Elevated circulating angiotensin (Ang) II levels, dietary sodium, and sympathetic stimulation are recurrent themes of hypertension research, but their in vivo interaction in physiologically meaningful doses has not been adequately investigated. In this study, the interaction of a subpressor dose of Ang II (50 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 SC), 2% NaCl diet, and sympathetic stimulation in the form of overnight cold exposure was investigated in the development of hypertension and of structural vascular changes in male Sprague-Dawley rats. There were 8 experimental groups: sham operation and treatment (control), Ang II, 2% NaCl diet, cold exposure (5°C), Ang II plus 2% NaCl diet, Ang II plus cold exposure, cold exposure plus 2% NaCl diet, and Ang II plus 2% NaCl diet plus cold exposure (triple treatment). For each group, the duration of treatment was 12 weeks. Morphometric measurements of maximally dilated, in situ fixed, second-order (250 to 320 m OD), intermediate-size (100 to 150 m OD), and small (50 to 100 m OD) mesenteric arteries were performed, and wall-to-lumen ratios (W/L) were calculated. During the 12-week study, the blood pressure (BP) load (the area under the systolic BP curve) of rats receiving the combined treatment of Ang II and 2% NaCl diet was increased (PϽ0.05), and that of rats receiving the combined treatment of cold exposure and 2% NaCl diet was decreased (PϽ0.05); there were no BP changes in the remaining groups of rats. The most pronounced changes among groups occurred in W/L of small resistance arteries. The W/L of small arteries increased in Ang II-treated (PϽ0.01) and in cold-stressed rats (PϽ0.01). The effect of Ang II was potentiated by the addition of a 2% NaCl diet. In contrast, the addition of 2% NaCl diet to cold stress reduced the W/L of small arteries (PϽ0.01). No other positive or negative synergism occurred among groups, including the rats receiving triple treatment. The findings confirm the potentiation of the hypertensinogenic and vascular trophic effects of Ang II by a high-sodium diet but do not provide evidence for synergism between Ang II and sympathetic stimulation. The finding of hypotension and reduced W/L of small resistance arteries in rats receiving the combined treatment of cold stress and high-sodium diet is unique because there are few known nonpharmacological vascular "hypotrophic" stimuli. The ultimate test of the hypertensinogenic potential of pressor stimuli alone or in combination is their long-term administration in physiologically meaningful doses to experimental animals. (Hypertension. 2001;37:255-260.)

Composite lymphoma (CL) describes the rare occurrence of 2 or more distinct types of lymphoma in a single anatomical location. We present the case of a 78-year-old man presenting with a 3-month history of weakness, malaise, and increasing dyspnea. A lymph node excised from the posterior triangle of the neck revealed the coexistence of 2 morphologically and phenotypically distinct lymphoid neoplasms consistent with a blastoid variant of mantle cell lymphoma (MCL) occurring in composite with classical Hodgkin lymphoma (cHL), mixed cellularity subtype. A t(11;14)(q13;q32) translocation was demonstrated by fluorescence in situ hybridization in the MCL and Hodgkin Reed-Sternberg cells of the cHL. Multiplex polymerase chain reaction detected clonal Immunoglobulin heavy chain (VFR1-J, VFR2-J, and VFR3-J), clonal immunoglobulin light chain kappa (V-J and V/JC intron-kde) and clonal immunoglobulin light chain lambda (V-J) gene rearrangements in the MCL. This report represents the first case of a blastoid variant of MCL occurring in composite with cHL.

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The hypothesis that long-term administration of a physiologically relevant high salt diet to rats leads to the development of structural vascular changes that predispose to hypertension was tested. Adult male Sprague-Dawley rats were fed 2% NaCl diet for 3 or 6 months; rats fed 0.7% NaCl diet were controls. Then, the systemic circulation of the rats was perfusion-fixed at 100 mm Hg. The junction of the mesentery and small intestine, the renal cortex, and segments of left carotid artery, thoracic aorta, and second order mesenteric arteries were embedded in paraffin or epoxy for morphometric measurements. The average monthly tail systolic blood pressure (BP) of salt-fed rats at 3 and 6 months were unchanged. The following morphometric changes in salt-fed rats were observed: 1) dilatation of the carotid artery at 3 months (P <.05); 2) dilatation and reduced wall-to-lumen ratio of the second order mesenteric artery (P <.01); 3) increased wall-to-lumen ratio of small mesenteric resistance arteries (P <.01); 4) reduced wall-to-lumen ratio of renal cortical resistance arteries at 6 months (P <. 05); and 5) unchanged structure of aorta. The long-term administration of a high salt diet leads to structural vascular changes in normotensive rats. There are important regional and segmental variations in the long-term adaptation of arteries to a high salt diet.