The addition of transdermal nicotine to conventional maintenance therapy improves symptoms in patients with ulcerative colitis.

Cell-associated proteoglycans provide highly complex and sophisticated systems to control interactions of extracellular cell matrix components and soluble ligands with the cell surface. Syndecans, a conserved family of heparan- and chondroitin-sulfate carrying transmembrane proteins, are emerging as central players in these interactions. Recent studies have demonstrated the essential role of syndecans in modulating cellular signaling in embryonic development, tumorigenesis, and angiogenesis. In this review, we focus on new advances in our understanding of syndecan-mediated cell signaling.

The extracellular matrix plays a number of important roles, among them providing structural support and information to cellular structures such as blood vessels imbedded within it. As more complex organisms have evolved, the matrix ability to direct signalling towards the vasculature and remodel in response to signalling from the vasculature has assumed progressively greater importance. This review will focus on the molecules of the extracellular matrix, specifically relating to vessel formation and their ability to signal to the surrounding cells to initiate or terminate processes involved in blood vessel formation.

Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4 −/− ) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4 −/− mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-κB was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-κB and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis. mechanotransduction | polarity | shear stress | atherosclerosis S yndecan 4 (S4) is a transmembrane heparan sulfate proteoglycan that serves as a coreceptor for extracellular matrix proteins and growth factors (1-3). S4−/− mice are viable and fertile (4, 5) but show defective wound healing consequent to impaired angiogenesis (6). They also have higher mortality after LPS injection (7) and exhibit defective muscle repair and myofiber organization as a result of inefficient differentiation and migration of muscle satellite cells (8). We and others have also demonstrated that S4 plays a critical role in the control of cell polarity, by controlling Rho GTPase activity (9-11), as well as in planar cell polarity (12). S4 has also been recently identified as a putative mechanosensor (13).Atherosclerosis is an inflammatory disease of large to midsized arteries that is the major cause of illness and death in developed nations and is rapidly increasing in developing nations (14,15). It is linked to a variety of risk factors including high LDL cholesterol level and triglycerides, diabetes, smoking, hypertension, sedentary lifestyle, and inflammatory mediators. However, atherosclerotic lesions occur selectively in regions of arteries that are subject to disturbances in fluid shear stress (FSS), the frictional force flowing blood exerts on the endothelium. Regions of arteries with lower flow magnitude, flow reversal, and other complex spatial/ temporal flow patterns are predisposed to atherosclerosis. Systemic risk factors appear to synergize with local biomechanical factors in the initiation and progression of atherosclerotic lesions (16).The importance of S4 in endothelial bi...

We suggest that chlormethiazole may have caused dysphagia by a direct action on the central mechanisms concerned in swallowing. Most reports of the adverse effects of this drug concentrate on the problems of drug abuse and addiction,3 and dysphagia has not been reported as a side effect. There have been some reports of dyspepsia, nausea, and vomiting related to the acidity of the tablets.4 This is unlikely to have been important in the present case, however, since no reflux was detected during overnight recording. Further studies are needed to investigate the prevalence and mechanism of oesophageal dysfunction in patients taking this drug.