Rottlerin inhibits P2X(7) receptor-stimulated phospholipase D activity in chronic lymphocytic leukaemia B-lymphocytes.

Phospholipase D (PLD) is a ubiquitous enzyme that can be activated by extracellular adenosine 5'-triphosphate (ATP) or phorbol 12-myristate 13-acetate (PMA) in B-lymphocytes from subjects with chronic lymphocytic leukaemia (CLL). In this study, ATP- but not PMA-induced PLD stimulation in CLL B-lymphocytes was abolished in the presence of an anti-P2X(7) receptor monoclonal antibody, as well as in B-lymphocytes from CLL subjects homozygous for the Glu(496) to Ala loss-of-function P2X(7) polymorphism. Rottlerin, an inhibitor of novel protein kinase C (PKC) isoforms, but not GF 109203X, an inhibitor of conventional PKC isoforms, impaired the ATP-stimulated PLD activity in CLL B-lymphocytes.

Human epidermal and monocyte-derived langerhans cells express functional P2X receptors.

Monocyte-derived dendritic cells (Mo-DC) express functional P2X7 receptors; however, the expression of these receptors on tissue-derived dendritic cells including epidermal Langerhans cells (LC) is unknown. Using immunolabeling and flow cytometry, we demonstrated that P2X7 was present on both human epidermal LC and monocyte-derived LC (Mo-LC), as well as on human keratinocytes. The ecto-ATPDase (CD39) was also present on LC, but not keratinocytes.

A 5' intronic splice site polymorphism leads to a null allele of the P2X7 gene in 1-2% of the Caucasian population.

The P2X(7) gene is important for the innate immune response but known polymorphisms do not explain all subjects with loss of P2X(7) function. A splice site mutation (g-->t) was found at position +1 of the first intron of the P2X(7) gene in 7 of 336 Caucasians and 1 of 39 subjects of Indian ethnicity. All eight subjects were heterozygous for the uncommon 1513A-->C polymorphism of the P2X(7) gene.

P2X7 receptor polymorphism impairs extracellular adenosine 5'-triphosphate-induced interleukin-18 release from human monocytes.

Interleukin (IL)-18 is an important proinflammatory cytokine processed and released from cells of the monocyte lineage by activation of the P2X(7) receptor by extracellular adenosine 5'-triphosphate (ATP). We examined if a loss-of-function polymorphism of the human P2X(7) receptor (glutamic acid-496 to alanine) impairs this process. Using a whole blood-based assay, ATP-induced release of IL-18 from homozygous subjects after 120 min incubation with ATP was 42% of that from wild-type subjects.

Extracellular ATP increases cation fluxes in human erythrocytes by activation of the P2X7 receptor.

Canine erythrocytes are known to undergo a reversible increase in cation permeability when incubated with extracellular ATP. We have examined the expression and function of P2X receptors on human erythrocytes using confocal microscopy and a panel of anti-P2X(1-7) antibodies and have measured monovalent cation fluxes in the presence of various nucleotide agonists. Human erythrocytes expressed P2X7 receptors on all cells examined from eight of eight subjects, as well as P2X2 at a far lower staining intensity in six of eight subjects.

Chelerythrine and other benzophenanthridine alkaloids block the human P2X7 receptor.

1 Extracellular ATP can activate a cation-selective channel/pore on human B-lymphocytes, known as the P2X7 receptor. Activation of this receptor is linked to PLD stimulation. We have used ATP-induced 86Rb+ (K+) efflux to examine the effect of benzophenanthridine alkaloids on P2X7 channel/pore function in human B-lymphocytes.

An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor.

The P2X(7) receptor is a ligand-gated channel that is highly expressed on mononuclear cells of the immune system and that mediates ATP-induced apoptosis. Wide variations in the function of the P2X receptor have been observed, explained in part by (7)loss-of-function polymorphisms that change Glu(496) to Ala (E496A) and Ile(568) to Asn (I568N). In this study, a third polymorphism, which substitutes an uncharged glutamine for the highly positively charged Arg(307) (R307Q), has been found in heterozygous dosage in 12 of 420 subjects studied.

Survey of the management of preterm labour in Australia and New Zealand in 2002.

Aim: To determine current attitudes and practices regarding the suppression of preterm labour among obstetricians in Australia and New Zealand.

Methods: A questionnaire mailed to all Diplomates, Members and Fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists in April 2002.

Results: A total of 813 surveys were returned - 33% (470/1412) of Fellows and Members and 11% (322/2806) of Diplomates.

Glu496 to Ala polymorphism in the P2X7 receptor impairs ATP-induced IL-1 beta release from human monocytes.

Priming of monocytes with LPS produces large quantities of intracellular, biologically inactive IL-1beta that can be processed and released by subsequent activation of the P2X7 receptor by extracellular ATP. We examined whether a loss-of-function polymorphism of the human P2X7 receptor (Glu496Ala) impairs this process. Both ATP-induced ethidium+ uptake and ATP-induced shedding of L-selectin (CD62L) were nearly absent in monocytes from four subjects homozygous for Glu496Ala confirming that this polymorphism impairs P2X7 function.

An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor.

The P2X(7) receptor is a ligand-gated channel that is highly expressed on mononuclear cells and that mediates ATP-induced apoptosis of these cells. Wide variations in the function of the P2X(7) receptor have been observed, in part because of a loss-of-function polymorphism that changes Glu-496 to Ala without affecting the surface expression of the receptor on lymphocytes. In this study a second polymorphism (Ile-568 to Asn) has been found in heterozygous dosage in three of 85 normal subjects and in three of 45 patients with chronic lymphocytic leukemia.

Liveliness.

Objective: The objective of this study is to explore the significance of the experience of liveliness in psychotherapeutic interactions and its relevance to the practice of psychotherapy.

Method: Stern's notion of 'vitality affects' and Emde's concept of a 'primary affective core' are employed in developing a concept of liveliness, or an enlivening-deadening axis of experience. A critique of Freud's 'principles of mental functioning' is made in the light of this concept.

A randomized clinical trial comparing oral misoprostol with synthetic oxytocin or syntometrine in the third stage of labour.

This is a multicentre, blocked, randomized trial to compare the efficacy of oral misoprostol 400 microg with current injectable uterotonic agents (oxytocin/ Syntometrine) used prophylactically in the third stage of labour. Main outcome measures were blood loss, use of a second uterotonic agent and difference in haemoglobin level from antepartum to postpartum. Data analysis from 863 women showed a statistically significant increase in both the mean blood loss (p < 0.

The impact of functional gastrointestinal disorders on quality of life.

Objective: The impact of functional gastrointestinal disorders (FGIDs) on quality of life is unknown. We aimed to evaluate whether FGIDs impair quality of life in terms of mental and physical functioning in patients and nonpatients.

Methods: A random sample of 4500 subjects, representative of the Australian population, were mailed a questionnaire on gastrointestinal symptoms in the past 12 months.

Evidence of a genetic contribution to functional bowel disorder.

Objective: Anecdotally, functional bowel disorders (FBD) such as the irritable bowel syndrome appears to cluster in some families, but no studies have investigated the heritability of FBD. We aimed to investigate the influence of heritable factors in FBD.

Methods: Same sex twin pairs enrolled in the Australian Twin Registry completed a structured interview that included questions related to symptoms consistent with FBD: abdominal pain, diarrhea, constipation, excessive gas or bloating, and nausea.