Impact of gender on the density of intraplaque neovascularization: a quantitative contrast-enhanced ultrasound study.

OBJECTIVE: Atherosclerosis is the main underlying cause of the majority of cardiovascular events. Although cardiovascular diseases (CVD) are a major challenge in both males and females, gender specific differences in the prevalence of CVD have been observed. This may indicate that there are differences in the development of atherosclerosis between males and females. The presence of intraplaque neovessels (IPN) is an imaging marker for plaque vulnerability. The aim of this study was to investigate the impact of gender on IPN. METHODS: A total of 159 patients with ≥1 cardiovascular risk factor were included in this prospective study (mean age 56.9±8.7 years, 47% females). Patients had no symptoms of carotid atherosclerotic disease. All patients underwent a standard carotid ultrasound examination in conjunction with contrast-enhanced ultrasound (CEUS). The presence of atherosclerotic plaques was assessed according to the Mannheim consensus. IPN was assessed using a visual grading scale and semi-automated quantification software. RESULTS: Subclinical atherosclerosis was detected using standard carotid ultrasound and CEUS in 64 females (86%) and in 79 males (93%) (p=0.177). The mean atherosclerotic plaque sizes were not significantly different (p=0.068). Semi-automated quantification of IPN demonstrated that females had significant more IPN compared to males (p<0.05). After adjustment for clinical variables this association remained significant (p<0.05). CONCLUSION: In this population at increased risk for CVD, females had significantly more IPN compared to males. This suggests that the females had a more vulnerable atherosclerotic plaque type.

MORT1/FADD is involved in liver regeneration.

AIM: To explore the role of the adaptor molecule in liver regeneration after partial hepatectomy (PH). METHODS: We used transgenic mice expressing an N-terminal truncated form of MORT1/FADD under the control of the albumin promoter. As previously shown, this transgenic protein abrogated CD95- and CD120a-mediated apoptosis in the liver. Cyclin A expression was detected using Western blotting. ELISA and RT-PCR were used to detect IL-6 and IL-6 mRNA, respectively. DNA synthesis in liver tissue was measured by BrdU staining. RESULTS: Resection of 70% of the liver was followed by a reduced early regenerative response in the transgenic group at 36 h. Accordingly, 36 h after hepatectomy, cyclin A expression was only detectable in wild-type animals. Consequently, the onset of liver mass restoration was retarded as measured by MRI volumetry and mortality was significantly higher in the transgenic group. CONCLUSION: Our data demonstrate for the first time an involvement of the death receptor molecule MORT1/FADD in liver regeneration, beyond its well described role as part of the intracellular death signaling pathway.

Control of organ transplant-associated graft-versus-host disease by activated host lymphocyte infusions.

BACKGROUND: Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal. METHODS: Graft-reactive host T cells were generated ex vivo from a patient suffering from a severe and refractory liver-transplant-associated GvHD. To control GvHD, activated alloreactive host T cells were repetitively retransferred into the patient (activated host lymphocyte infusion [aHLI]). RESULTS: Adoptive transfer of ex vivo activated alloreactive host T cells (aHLI) led to the control and complete resolution of severe GvHD without inducing allograft rejection. CONCLUSIONS: aHLI opens a novel therapeutic window to control solid-organ transplant-associated GvHD while preserving allograft integrity.

TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.

Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.

Essential thrombocythemia terminating in pure erythroleukemia.

Transformation into acute leukemia is a rare event in essential thrombocythemia (ET). The blasts are usually of myeloid, rarely of megakaryoblastic differentiation. We present the case of a patient with pure erythroleukemia after a nearly 10-year course of ET, which was treated with hydroxyurea. The patient, a 58-year-old male, presented with an elevated thrombocyte count (926,000/microL) and normal values of hemoglobin and leukocytes. After 10 years of therapy with hydroxyurea, the patient developed acute leukemia of solely erythroid differentiation. Chemotherapy with cytarabine and daunorubicin resulted in incomplete remission. The patient died 2 months after diagnosis of acute erythroleukemia. Transformation of ET into erythroleukemia may demonstrate the pluripotent potential of the neoplastic hemopoietic stem cell, with the ability to cause acute leukemia not only of myeloid or megakaryoblastic but also of erythroid lineage.

Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure.

BACKGROUND/AIMS: Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published. METHODS: A retrospective analysis was performed of patients treated for liver disease between 1992 and 2002 at our department to evaluate the incidence, clinical findings and histopathology of coumarin-induced hepatotoxicity. RESULTS: The retrospective analysis revealed eight cases of phenprocoumon-induced hepatotoxicity, including three cases of (sub-) acute liver failure which resulted in two orthotopic liver transplantations and one fatal outcome. Five patients with phenprocoumon-induced hepatitis recovered well after anticoagulation was switched to another coumarin derivate or subcutaneous low molecular weight heparin. In all patients liver injury was predominantly of an hepatitic type. In the cases of (sub-) acute liver failure massive confluent liver cell necroses were histologically present, whereas among patients without liver failure mild portal to moderate active lobular hepatitis were observed. A retrospective analysis by BfArM (German Federal Institute for Drugs and Medical Devices) revealed 4390 cases of possible phenprocoumon-related adverse reactions since 1990, 2% of which had presented with hepatitis and 0.2% with liver failure. CONCLUSIONS: Phenprocoumon-induced liver disease is an uncommon complication, which can, however, cause (sub-) acute liver failure.

TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo.

Factors influencing the development of CD4+CD25+ T-cells in vivo are poorly understood. In order to investigate the contribution of TGFbeta1 to the development and function of CD4+CD25+ T-cells, we generated a gain of function mutation resulting in the overexpression of an active form of TGFbeta1 in T-cells under control of the human CD2 promoter. In peripheral lymphoid organs and in the thymus, the frequency of CD4+CD25+ T-cells was increased in transgenic mice. This appeared to be due to an autocrine effect of TGFbeta on T-cells, since concomitant impairment of TGFbeta-signaling in double transgenic mice resulted in a phenotype similar to wild type. In contrast, in single transgenic mice with impaired TGFbeta-signaling in T-cells, CD4+CD25+ T-cell numbers were reduced in peripheral lymphoid organs but not in the thymus. In addition, TGFbeta was found to regulate the expression of Foxp3 in vivo, a transcription factor essential for the generation and function of regulatory T-cells. In CD4+CD25+ T-cells, TGFbeta1 increased the expression of Foxp3, whereas a decreased expression was seen in CD4+CD25+ T-cells with impaired TGFbeta-signaling. TGFbeta1 induced the expression of IL-10 in transgenic T-cells, but the increased in vitro suppressive capacity observed in transgenic CD4+CD25+ T-cells was due to the secretion of TGFbeta and not IL-10. Therefore, our study provides in vivo evidence for a role of TGFbeta in the homeostasis of CD4+CD25+ T-cells.

GM-CSF expression by human lung microvascular endothelial cells: in vitro and in vivo findings.

Recently, many findings indicate that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the pathogenesis of acute and chronic lung diseases. In the present paper, the production of this cytokine in human pulmonary microvascular endothelial cells (HPMEC) is investigated. In an in vitro study, quiescent HPMEC did not express GM-CSF, either at the transcriptional or at the protein level. After activation for 4 h with tumor necrosis factor (TNF)-alpha (30/300 U/ml), lipopolysaccharide (LPS; 0.1/1 microg/ml), or interleukin (IL)-1 beta (100 U/ml), a significant release of GM-CSF was measured by enzyme-linked immunosorbent assay, with a time-dependent increase over 72 h. IL-8 (4, 16, or 64 ng/ml) or IL-1 beta at a concentration of 10 U/ml did not induce the release of GM-CSF. Human umbilical vein endothelial cells (HUVEC) and the angiosarcoma cell line HAEND served as reference cell lines. GM-CSF release in HPMEC was significantly (P < 0.025-0.05) less inducible by IL-1 beta than in HUVEC. A constitutive expression of GM-CSF by HAEND was observed. Additionally, GM-CSF expression in vivo by the lung microvasculature was confirmed by immunohistochemistry in lung tissue. To our knowledge, this is the first report of the ability of human pulmonary endothelial cells to synthesize and release GM-CSF. These results support the hypothesis that the lung microvasculature via the production of GM-CSF is a potential contributor to the cytokine network in lung diseases. This could be of particular importance in the pathogenesis of the acute respiratory distress syndrome in which endothelial dysfunction plays a central pathogenetic role.