Inflammation occurs as a result of exposure of tissues and organs to harmful stimuli such as microbial pathogens, irritants, or toxic cellular components. The primary physical manifestations of inflammation are redness, swelling, heat, pain, and loss of function to the affected area. These processes involve the major cells of the immune system, including monocytes, macrophages, neutrophils, basophils, dendritic cells, mast cells, T-cells, and B-cells. However, examination of a range of inflammatory lesions demonstrates the presence of specific leukocytes in any given lesion. That is, the inflammatory process is regulated in such a way as to ensure that the appropriate leukocytes are recruited. These events are in turn controlled by a host of extracellular molecular regulators, including members of the cytokine and chemokine families that mediate both immune cell recruitment and complex intracellular signalling control mechanisms that characterise inflammation. This review will focus on the role of the main cytokines, chemokines, and their receptors in the pathophysiology of auto-inflammatory disorders, pro-inflammatory disorders, and neurological disorders involving inflammation.

Tissue barriers that restrict passage of liquids, ions, and larger solutes are essential for the development of multicellular organisms. In simple organisms this allows distinct cell types to interface with the external environment. In more complex species, the diversity of cell types capable of forming barriers increases dramatically. Although the plasma membranes of these barrier-forming cells prevent flux of most hydrophilic solutes, the paracellular, or shunt, pathway between cells must also be sealed. This function is accomplished in vertebrates by the zonula occludens, or tight junction. The tight junction barrier is not absolute but is selectively permeable and is able to discriminate between solutes on the basis of size and charge. Many tight junction components have been identified over the past 20 years, and recent progress has provided new insights into the proteins and interactions that regulate structure and function. This review presents these data in a historical context and proposes an integrated model in which dynamic regulation of tight junction protein interactions determines barrier function.

Epithelia form barriers that are essential to life. This is particularly true in the intestine, where the epithelial barrier supports nutrient and water transport while preventing microbial contamination of the interstitial tissues. Along with plasma membranes, the intercellular tight junction is the primary cellular determinant of epithelial barrier function. Disruption of tight junction structure, as a result of specific protein mutations or aberrant regulatory signals, can be both a cause and an effect of disease. Recent advances have provided new insights into the extracellular signals and intracellular mediators of tight junction regulation in disease states as well as into the interactions of intestinal barrier function with mucosal immune cells and luminal microbiota. In this review, we discuss the critical roles of the tight junction in health and explore the contributions of barrier dysfunction to disease pathogenesis.

We modify the standard model for big-bang nucleosynthesis to allow for the presence of a generic particle species, i.e., one which maintains good thermal contact with either the photons or the lightneutrino species throughout the epoch of primordial nucleosynthesis. The production of D, 'He, 4He, and 'Li is calculated as a function of the mass, degrees of freedom, and spin statistics of the generic particle. We show that in general, the effect of an additional generic species cannot simply be parametrized as the equivalent number of additional light-neutrino species. The presence of generic particles also affects the predicted value for the neutrino-to-photon temperature ratio.

Phosphoinositide 3-kinases (PI3Ks) are critical regulators of pancreatic β cell mass and survival, whereas their involvement in insulin secretion is more controversial. Furthermore, of the different PI3Ks, the class II isoforms were detected in β cells, although their role is still not well understood. Here we show that down-regulation of the class II PI3K isoform PI3K-C2α specifically impairs insulin granule exocytosis in rat insulinoma cells without affecting insulin content, the number of insulin granules at the plasma membrane, or the expression levels of key proteins involved in insulin secretion. Proteolysis of synaptosomal-associated protein of 25 kDa, a process involved in insulin granule exocytosis, is impaired in cells lacking PI3K-C2α. Finally, our data suggest that the mRNA for PI3K-C2α may be down-regulated in islets of Langerhans from type 2 diabetic compared with non-diabetic individuals. Our results reveal a critical role for PI3K-C2α in β cells and suggest that down-regulation of PI3K-C2α may be a feature of type 2 diabetes.

Despite careful selection of patients with non-functioning pituitary adenomas, tumour regrowth occurs in a significant proportion. These results show that continued follow-up in these patients is essential as significantly more patients showed evidence of tumour regrowth at this second assessment compared with the 1994 data. Until we are able to predict which tumours are likely to regrow postoperatively, radiotherapy should be considered for all patients with non-functioning pituitary adenomas as even in carefully selected cases, the regrowth rate is approaching 50% at 10 years.

Calpain-10 (CAPN10) is the first type 2 diabetes susceptibility gene to be identified through a genome scan, with polymorphisms being associated with altered CAPN10 expression. Functional data have been hitherto elusive, but we report here a corresponding increase between CAPN10 expression level and regulated insulin secretion. Pancreatic beta-cell secretory granule exocytosis is mediated by the soluble N-ethylmaleimide-sensitive fusion protein attachment receptor protein complex of synaptosomal-associated protein of 25 kDa (SNAP-25), syntaxin 1, and vesicle-associated membrane protein 2. We report, for the first time, direct binding of a calpain-10 isoform with members of this complex. Furthermore, SNAP-25 undergoes a Ca2+-dependent partial proteolysis during exocytosis, with calpain protease inhibitor similarly suppressing both insulin secretion and SNAP-25 proteolysis. Based upon these findings, we postulate that an isoform of calpain-10 is a Ca2+-sensor that functions to trigger exocytosis in pancreatic beta-cells.

Studies that have attempted to measure the effects of prehospital intravenous fluids have predominantly used crystalloid infusion as recommended by American Advanced Trauma Life Support guidelines. 13 There are several disadvantages to this strategy. Computerised modelling of intravenous fluid therapy has suggested that potential benefits of crystalloid infusion will only occur if there is a bleeding rate of 25-100 ml/min, the rate of fluid infusion is at least equal to the bleeding rate, and if the prehospital time exceeds 30 minutes. 14 In practice, these criteria are unlikely to be met. One study