The priming effect of extracellular UTP on human neutrophils: Role of calcium released from thapsigargin-sensitive intracellular stores

P2Y2 receptors, which are equally responsive to ATP and UTP, can trigger intracellular signaling events, such as intracellular calcium mobilization and mitogen-activated protein (MAP) kinase phosphorylation in polymorphonuclear leukocytes (PMN). Moreover, extracellular nucleotides have been shown to prime chemoattractant-induced superoxide production. The aim of our study was to investigate the mechanism responsible for the priming effect of extracellular nucleotides on reactive oxygen species (ROS) production induced in human neutrophils by two different chemoattractants: formyl-methionyl-leucyl-phenylalanine (fMLP) and interleukin-8 (IL-8). Nucleotide-induced priming of ROS production was concentration- and time-dependent. When UTP was added to neutrophil suspensions prior to chemoattractant, the increase of the response reached the maximum at 1 min of pre-incubation with the nucleotide. UTP potentiated the phosphorylation of p44/42 and p38 MAP kinases induced by chemoattractants, however the P2 receptor-mediated potentiation of ROS production was still detectable in the presence of a SB203580 or U0126, supporting the view that MAP kinases do not play a major role in regulating the nucleotide-induced effect. In the presence of thapsigargin, an inhibitor of the ubiquitous sarco-endoplasmic reticulum Ca2+-ATPases in mammalian cells, the effect of fMLP was not affected, but UTP-induced priming was abolished, suggesting that the release of calcium from thapsigargin-sensitive intracellular stores is essential for nucleotide-induced priming in human neutrophils

Chronic Granulomatous Disease; fundamental stages in our understanding of CGD

It has been 50 years since chronic granulomatous disease was first reported as a disease which fatally affected the ability of children to survive infections. Various milestone discoveries from the insufficient ability of patients' leucocytes to destroy microbial particles to the underlying genetic predispositions through which the disease is inherited have had important consequences. Longterm antibiotic prophylaxis has helped to fight infections associated with chronic granulomatous disease while the steady progress in bone marrow transplantation and the prospect of gene therapy are hailed as long awaited permanent treatment options. This review unearths the important findings by scientists that have led to our current understanding of the disease

Rac and Rho GTPases in cancer cell motility control

Rho GTPases represent a family of small GTP-binding proteins involved in cell cytoskeleton organization, migration, transcription, and proliferation. A common theme of these processes is a dynamic reorganization of actin cytoskeleton which has now emerged as a major switch control mainly carried out by Rho and Rac GTPase subfamilies, playing an acknowledged role in adaptation of cell motility to the microenvironment. Cells exhibit three distinct modes of migration when invading the 3 D environment. Collective motility leads to movement of cohorts of cells which maintain the adherens junctions and move by photolytic degradation of matrix barriers. Single cell mesenchymal-type movement is characterized by an elongated cellular shape and again requires extracellular proteolysis and integrin engagement. In addition it depends on Rac1-mediated cell polarization and lamellipodia formation. Conversely, in amoeboid movement cells have a rounded morphology, the movement is independent from proteases but requires high Rho GTPase to drive elevated levels of actomyosin contractility. These two modes of cell movement are interconvertible and several moving cells, including tumor cells, show an high degree of plasticity in motility styles shifting ad hoc between mesenchymal or amoeboid movements. This review will focus on the role of Rac and Rho small GTPases in cell motility and in the complex relationship driving the reciprocal control between Rac and Rho granting for the opportunistic motile behaviour of aggressive cancer cells. In addition we analyse the role of these GTPases in cancer progression and metastatic dissemination

A randomised controlled trial of a cognitive behavioural therapy based self-management intervention for irritable bowel syndrome (IBS) in primary care.

Background: recent guidelines for the treatment of irritable bowel syndrome (IBS) emphasize the need for research to facilitate home-based self-management for these patients in primary care. The aim of the current study was to test the efficacy of a manualized cognitive behavioural therapy (CBT)-based self-management programme for IBS in a pilot randomized controlled trial (RCT).Method: sixty-four primary-care patients meeting Rome criteria for IBS were randomized into either self-management plus treatment as usual (TAU) (n=31) or a TAU control condition (n=33). The self-management condition included a structured 7-week manualized programme that was self-administered in conjunction with a 1-hour face-to-face therapy session and two 1-hour telephone sessions. The primary outcome measures were the Subject's Global Assessment (SGA) of Relief and the Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) assessed at baseline, end of treatment (2 months), and 3 and 6 months post-treatment.Results: analysis was by intention-to-treat. Twenty-three (76.7%) of the self-management group rated themselves as experiencing symptom relief across all three time periods compared to seven (21.2%) of the TAU controls [odds ratio (OR) 12.2, 95% confidence interval (CI) 3.72–40.1]. At 8 months, 25 (83%) of the self-management group showed a clinically significant change on the IBS-SSS compared to 16 (49%) of the control group (OR 5.3, 95% CI 1.64–17.26).Conclusions: this study provides preliminary evidence that CBT-based self-management in the form of a structured manual and minimal therapist contact is an effective and acceptable form of treatment for primary-care IBS patients.<br/

Bronze age cremations, Iron Age and Roman settlement and early Medieval inhumations at the Langeled receiving facilities, Easington, East Riding of Yorkshire

Excavations to the north of the village of Easington in the East Riding of Yorkshire identified a funerary landscape of Late Bronze Age, Later Iron Age and Roman cremations, as well as Roman and early medieval inhumations. The four early medieval burials included a spearhead, knives, buckles and beads. Occupation activity associated with the Bronze Age and early medieval burials was not identified, but a 'ladder-style' settlement of trackways and enclosures was established by the first century BC. This settlement underwent at least two episodes of restructuring before its abandonment, probably in the third century AD. Given a dearth of imported objects and the preservation of pre-Conquest-style building traditions, the inhabitants of the final settlement chose not to adopt the trappings of a 'Romanised' lifestyle