The development of varicose veins or chronic venous insufficiency is preceded by and associated with the pathophysiological remodelling of the venous wall. Recent work suggests that an increase in venous filling pressure is sufficient to promote varicose remodelling of veins by augmenting wall stress and activating venous endothelial and smooth muscle cells. In line with this, known risk factors such as prolonged standing or an obesity-induced increase in venous filling pressure may contribute to varicosis. This review focuses on biomechanically mediated mechanisms such as an increase in wall stress caused by venous hypertension or alterations in blood flow, which may be involved in the onset of varicose vein development. Finally, possible therapeutic options to counteract or delay the progress of this venous disease are discussed.

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To investigate the effect of tumor-associated macrophages on the in vivo growth properties of cervical carcinoma cells, tumorigenic human papilloma virus (HPV) 18-positive HeLa cells were transfected with an expression vector harboring the cDNA for the macrophage chemoattractant protein-1 JE (MCP-1). Although the endogenous gene is present and not structurally rearranged, its expression seems to be negatively affected by a still unknown mechanism. Inoculation of JE (MCP-1)-negative HeLa cells into nude mice led to rapidly growing tumors, where macrophage infiltration into the inner tumor mass was not detectable immunohistochemically. The activity that attracted mononuclear cells under both in vitro and in vivo condition was reconstituted in HeLa cells after transfection with the JE (MCP-1) expression vector. Heterotransplantation of those cells into immunocompromised animals resulted in significant growth retardation that was accompanied by a strong infiltration of macrophages. On the other hand, in vivo selection of nonmalignant hybrids made between wild-type HeLa cells and normal human fibroblasts in nude mice resulted in tumorigenic segregants 4 mo after inoculation into the animals. Monitoring JE (MCP-1) expression directly within those nodules, we found that transcription was either absent or only weakly detectable. Recultivation of JE (MCP-1)-positive tissue grafts under in vitro conditions revealed that the gene was only marginally inducible by tumor necrosis factor-alpha, a cytokine that normally induces a very strong activation of transcription in nontumorigenic cells. These findings suggest that functional JE (MCP-1) expression and in turn activated macrophages may play a pivotal role in controlling the proliferation rate of HPV-positive cells in vivo.

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We propose a further refinement of the the non‐homogeneous Gaussian regression approach for temperature, which transforms the output of an ensemble prediction system into predictive Gaussian distributions at each location of interest. Model fitting is partly done within a regression framework using a penalized version of the least‐squares loss function. This is conceptually simpler than the original approach and at the same time is able to prevent overfitting. While calibration is initially performed at observation locations only, geostatistical methods are used to provide predictive distributions on the entire grid. The incorporation of land‐use information in this interpolation scheme further improves predictive performance, even though a simpler statistical model than in the original approach is used. The assessment of predictive performance and calibration is carried out with dynamical forecasts of 2 m temperatures by the COSMO‐DE‐EPS, an application of the COSMO (Consortium for Small‐scale Modeling) model system which covers Germany and neighbouring countries.