Living with genital Pain: women's experience of treatment seeking

Female Genital Pain (FGP) is a sexual dysfunction that is difficult to diagnose and treat, which can make treatment seeking a distressing experience. In the present study the lived experience of women with genital pain as explored in order to develop a grounded model of treatment seeking for FGP. A constructivist lived experience perspective underpinned this research. Participants were 26 women with genital pain, specifically vaginismus (n=4) and (n=22). The average age of the participants was 27. Identified motivations for seeking treatment were the belief that they might have an infection, optimistic views about their health or an expectation that relationships include intercourse. Barriers occurred when they normalised or discounted their symptoms or held negative treatment beliefs. Unsurprisingly, the identified barriers were associated with delayed treatment seeking. The women described three agendas for their consultation with a health care professional (HCP) – validation of their symptoms, an informed HCP, and a strong HCP–patient alliance. Agendas that were met played a significant role in decreasing distress. Identified salient survivorship resources were a supportive HCP and personal agency. These resources encouraged consistent treatment seeking. The personal narratives that contributed to more consistent treatment seeking were personal agency, communion, redemption, creating meaning of suffering, positive sexual identity and positive resolution. Identities that were characterised by contamination and negative sexual self-schema were associated with no treatment seeking or delayed treatment seeking. The findings of this study allow HCPs and researchers to better understand the needs of women with genital pain. Furthermore, this research will help guide future research and the development of future initiatives to improve the treatment of genital pain conditions, thus improving the outcomes and quality of life for women with genital pain

Cytokine-mediated cPLA2 phosphorylation is regulated by multiple MAPK family members

Cytosolic phospholipase A2 (cPLA2) plays a critical role in various neutrophil functions including the generation of leukotrienes and platelet-activating factor release. Enzyme activity is regulated both by translocation to the membrane in a Ca^(2+) -dependent manner and serine phosphorylation by members of the mitogen-activated protein kinase (MAPK) family. In this report, we have investigated the role of granulocyte/macrophage colony-stimulating factor (GM-CSF)- mediated signalling pathways in the regulation of cPLA2. GM- CSF-induced cPLA2 phosphorylation was not affected by pharmacological inhibition of p38 MAPK, phosphatidylinositol 3-kinase or Src. However, inhibition of extracellular signal- regulated kinase (ERK) MAPK activation resulted in a partial inhibition of cPLA2 phosphorylation, revealed in a slower onset of phosphorylation. A cell line stably transfected with the GM- CSF receptor was used to further analyze GM-CSF-mediated cPLA2 phosphorylation. Mutation of tyrosine residues 577 and 612 resulted in a delayed cPLA2 phosphorylation similar to the pharmacological ERK inhibition. Furthermore, inhibition of p38 MAPK in cells bearing the double mutant ßc577/612 completely abrogated GM-CSF-induced cPLA2 phosphorylation. We con- clude that GM-CSF can mediate cPLA2 phosphorylation through the redundant activation of both p38 and ERK MAP kinases

Are Ecosystem Engineering Traits Fixed or Flexible : A Study on Clonal Expansion Strategies in Co-occurring Dune Grasses

Many vegetated coastal ecosystems are formed through ecosystem engineering by clonal vegetation. Recent work highlights that the spatial shoot organization of the vegetation determines local sediment accretion and subsequently emerging landscape morphology. While this key engineering trait has been found to differ between species and prevailing environmental conditions, it remains unknown how the interplay of both factors drive shoot organization and therefore landscape morphology. Here, we compared the spatial shoot organization of young, clonally expanding plants of the two dominant European dune grass species: sand couch (Elytrigia juncea) and marram grass (Ammophila arenaria) across a range of coastal dune environments (from Denmark to France). Our results reveal that, on average, sand couch deployed a more dispersed shoot organization than marram grass, which has a patchy (Lévy-like) organization. Whereas sand couch exhibited the same expansion strategy independent of environmental conditions, marram grass demonstrated a large intraspecific variation which correlated to soil organic matter, temperature and grain size. Shoot patterns ranged from a clumped organization correlating to relatively high soil organic matter contents, temperature and small grain sizes, to a patchy configuration with intermediate conditions, and a dispersed organization with low soil organic matter, temperature and large grain size. We conclude that marram grass is flexible in adjusting its engineering capacity in response to environmental conditions, while sand couch instead follows a fixed expansion strategy, illustrating that shoot organization results from the interaction of both species-specific and environmental-specific trait expression

Comparison of the roles of mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signal transduction in neutrophil effector function

Although it is known that many stimuli can activate mitogen- activated protein kinases (MAPKs) and phosphatidylinositol 3- kinases (PI3K) in human neutrophils, little is known concerning either the mechanisms or function of this activation. We have utilized a selective inhibitor of MAPKkinase (MEK), PD098059, and two inhibitors of PI3K, wortmannin and LY294002, to investigate the roles of these kinases in the regulation of neutrophil effector functions. Granulocyte/macrophage colony- stimulating factor, platelet-activating factor (PAF) and N-for- mylmethionyl-leucyl-phenylalanine are capable of activating both p44^(ERK1) and p42^(ERK2) MAPKs and phosphotyrosine-asso- ciated PI3K in human neutrophils. The activation of extracellular signal-related protein kinases (ERKs) is correlated with the activation of p21^(ras) by both tyrosine kinase and G-protein- coupled receptors as measured by a novel assay for GTP loading. Wortmannin and LY294002 inhibit, to various degrees, super- oxide generation, neutrophil migration and PAF release. In- cubation with PD098059, however, inhibits only the PAF release stimulated by serum-treated zymosan. This demonstrates that, while neither MEK nor ERK kinases are involved in the acti- vation of respiratory burst or neutrophil migration, inhibition of PAF release suggests a potential role in the activation of cytosolic phospholipase A2 . PI3K isoforms, however, seem to have a much wider role in regulating neutrophil functioning

Structural and Biophysical Insights into SPINK1 Bound to Human Cationic Trypsin

(1) The serine protease inhibitor Kazal type 1 (SPINK1) inhibits trypsin activity in zymogen granules of pancreatic acinar cells. Several mutations in the SPINK1 gene are associated with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). The most common variant is SPINK1 p.N34S. Although this mutation was identified two decades ago, the mechanism of action has remained elusive. (2) SPINK1 and human cationic trypsin (TRY1) were expressed in E. coli, and inhibitory activities were determined. Crystals of SPINK1–TRY1 complexes were grown by using the hanging-drop method, and phases were solved by molecular replacement. (3) Both SPINK1 variants show similar inhibitory behavior toward TRY1. The crystal structures are almost identical, with minor differences in the mutated loop. Both complexes show an unexpected rotamer conformation of the His63 residue in TRY1, which is a member of the catalytic triad. (4) The SPINK1 p.N34S mutation does not affect the inhibitory behavior or the overall structure of the protein. Therefore, the pathophysiological mechanism of action of the p.N34S variant cannot be explained mechanistically or structurally at the protein level. The observed histidine conformation is part of a mechanism for SPINK1 that can explain the exceptional proteolytic stability of this inhibitor