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Biomedical subjects

Helen Turner

Publications and source records attributed to Helen Turner.

18 recordsLinked to original sources
PubMed2006

TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD.

Certain TRP cation channels confer the ability to sense environmental stimuli (heat, cold, pressure, osmolarity) across physiological and pathophysiological ranges. TRPA1 is a TRP-related channel that responds to cold temperatures, and pungent compounds that include the cold-mimetic icilin and cannabinoids. The initial report of TRPA1 as a transformation-associated gene product in lung epithelia is at odds with subsequent descriptions of a tissue distribution for TRPA1 that is restricted to sensory neurons. Here, we report that the human TRPA1 protein is widely expressed outside the CNS, and is indeed dys-regulated during oncogenic transformation. We describe that TRPA1 associates with the tumor-suppressor protein CYLD. TRPA1 is a novel substrate for the de-ubiquitinating activity of CYLD, and this de-ubiquitination has the net effect of increasing the cellular pool of TRPA1 proteins. Oncogenic mutations in the CYLD gene may therefore be predicted to alter cellular levels of TRPA1.

Calcium Channels↗
PubMed2006

Literature review: Afghanistan women's health crisis, health service delivery, and ethical issues for international aid.

The literature indicates that the health of women in Afghanistan is poor. In 1997 maternal mortality in Afghanistan was one of the worst in the world. Difficulties in establishing health services revolve around fundamentalist Islamic ideas and ongoing violence within Afghanistan. The literature holds advice on key behaviours for health professionals who may chose to work in Afghanistan. The literature also identifies the local level action that is occurring as the issue of women's health is recognised. Humanitarian assistance has been provided, with international aid agencies having to weigh the ethical responsibilities they hold and one agency tragically facing the violent loss of its own staff. Easy answers are not in the literature, merely an opportunity to understand, consider, and take action about what is facing women in Afghanistan and those who try to help.

Afghanistan↗
PubMed2005

Fcepsilon RI control of Ras via inositol (1,4,5) trisphosphate 3-kinase and inositol tetrakisphosphate.

The inositol (1,4,5) trisphosphate 3-kinase (ITP3K) phosphorylates Ins (1,4,5) P3 to produce Ins (1,3,4,5) P4. The ITP3K substrate, InsP3, and its product, InsP4, both have the potential to regulate mast cell function. Here, we explore the effects of dominant inhibition of ITP3K upon secretory responses and Ras GTPase activation following antigenic cross-linking of the mast cell immunoreceptor, FcvarepsilonRI. Inhibition of ITP3K potentiates both calcium release from intracellular stores and calcium-dependent secretory responses in mast cells. Moreover, mast cells with dominantly inhibited ITP3K display constitutive activation of Ras and certain Ras effector pathways. We propose three mechanisms by which ITP3K inhibition could influence Ras activation. The protection of InsP3 that results from ITP3K inhibition may lead to enhanced activation of calcium-sensitive Ras-GAPs or -GRFs. Similarly, the deficit in InsP4 may change the behavior of the InsP4 receptor, the GAP1(IP4BP). Our data are inconsistent with calcium-sensitive Ras-GAP activation being the primary consequence of ITP3K inhibition in mast cells. Rather, we observe potentiation of Ras responses in mast cells transfected with dominant negative GAP1(IP4BP). Moreover, shRNA-mediated knockdown of GAP1(IP4BP) potentiates FcvarepsilonRI-mediated Ras activation, indicating that this InsP4-binding GAP protein may be used by the FcvarepsilonRI immunoreceptor to regulate Ras.

Animals↗
PubMed2005

Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells.

Cannabinoids are broadly immunosuppressive, and anti-inflammatory properties have been reported for certain marijuana constituents and endogenously produced cannabinoids. The CB2 cannabinoid receptor is an established constituent of immune system cells, and we have recently established that the CB1 cannabinoid receptor is expressed in mast cells. In the present study, we sought to define a role for CB1 in mast cells and to identify the signalling pathways that may mediate the suppressive effects of CB1 ligation on mast cell activation. Our results show that CB1 and CB2 mediate diametrically opposed effects on cAMP levels in mast cells. The observed long-term stimulation of cAMP levels by the Galpha(i/o)-coupled CB1 is paradoxical, and our results indicate that it may be attributed to CB1-mediated transcriptional regulation of specific adenylate cyclase isoenzymes that exhibit superactivatable kinetics. Taken together, these results reveal the complexity in signalling of natively co-expressed cannabinoid receptors and suggest that some anti-inflammatory effects of CB1 ligands may be attributable to sustained cAMP elevation that, in turn, causes suppression of mast cell degranulation.

Adenylyl Cyclases↗
PubMed2005

Exposure to tobacco-derived materials induces overproduction of secreted proteinases in mast cells.

Mast cells reside at interfaces with the environment, including the mucosa of the respiratory and gastrointestinal tracts. This localization exposes mast cells to inhaled, or ingested, environmental challenges. In the airways of smokers, resident immune cells will be in contact with the condensed components of cigarette smoke. Mast cells are of particular interest due to their ability to promote airway remodeling and mucus hypersecretion. Clinical data show increased levels of mast cell-secreted tryptase and increased numbers of degranulated mast cells in the lavage and bronchial tissue of smokers. Since mast cell-secreted proteinases (MCPTs), including tryptases, contribute to pathological airway remodeling, we investigated the relationship between mast cell proteinases and smoke exposure. We exposed a mast cell line to cigarette smoke condensate (CSC). We show that CSC exposure increases MCPT levels in mast cells using an assay for tryptase-type MCPT activity. We hypothesized that this increase in MCPT activity reflects a CSC-induced increase in the cytosolic pool of proteinase molecules, via stimulation of MCPT transcription. Transcript array data suggested that mRNA changes in response to CSC were limited in number and peaked after 3 h of CSC exposure. However, we noted marked transcriptional regulation of several MCPT genes. CSC-induced changes in the mRNA levels for MCPTs were confirmed using quantitative RT-PCR. Taken together, our data suggest that chronic exposure to cigarette smoke up-regulates MCPT levels in mast cells at both the protein and the mRNA level. We suggest that the pathological airway remodeling that has been described in clinical studies of smoke inhalation may be attributable to MCPT overproduction in vivo.

Cell Line↗
PubMed2005

Formation of a physiological complex between TRPV2 and RGA protein promotes cell surface expression of TRPV2.

The transient receptor potential, sub-family Vanilloid (TRPV)(2) cation channel is activated in response to extreme temperature elevations in sensory neurons. However, TRPV2 is widely expressed in tissues with no sensory function, including cells of the immune system. Regulation of GRC, the murine homolog of TRPV2 has been studied in insulinoma cells and myocytes. GRC is activated in response to certain growth factors and neuropeptides, via a mechanism that involves regulated access of the channel to the plasma membrane. This is likely to be an important primary control mechanism for TRPV2 outside the CNS. Here, we report that a regulated trafficking step controls the access of TRPV2 to the cell surface in mast cells. In mast cells, elevations in cytosolic cAMP are sufficient to drive plasma membrane localization of TRPV2. We have previously proposed that the recombinase gene activator protein (RGA), a four-transmembrane domain, intracellular protein, associates with TRPV2 during the biosynthesis and early trafficking of the channel. We use a polyclonal antibody to RGA to confirm the formation of a physiological complex between RGA and TRPV2. Finally, we show that over-expression of the RGA protein potentiates the basal surface localization of TRPV2. We propose that trafficking and activation mechanisms intersect for TRPV2, and that cAMP mobilizing stimuli may regulate TRPV2 localization in non-sensory cells. RGA participates in the control of TRPV2 surface levels, and co-expression of RGA may be a key component of experimental systems that seek to study TRPV2 physiology.

Animals↗
PubMed2005

Binding of HTm4 to cyclin-dependent kinase (Cdk)-associated phosphatase (KAP).Cdk2.cyclin A complex enhances the phosphatase activity of KAP, dissociates cyclin A, and facilitates KAP dephosphorylation of Cdk2.

Cyclin-dependent kinase 2 (cdk2) activation requires phosphorylation of Thr160 and dissociation from cyclin A. The T-loop of cdk2 contains a regulatory phosphorylation site at Thr160. An interaction between cdc-associated phosphatase (KAP) and cdk2 compromises the interaction between cdk2 and cyclin A, which permits access of KAP, a Thr160-directed phosphatase, to its substrate, cdk2. We have reported that KAP is bound and activated by a nuclear membrane protein, HTm4. Here, we present in vitro data showing the direct interaction between the HTm4 C terminus and KAP Tyr141. We show that this interaction not only facilitates access of KAP to Thr160 and accelerates KAP kinetics, but also forces exclusion of cyclin A from the KAP.cdk2 complex.

Amino Acid Sequence↗
PubMed2005

Assessment of acute and chronic pain symptoms in children with cystic fibrosis.

Pain is important to assess and treat in children with cystic fibrosis (CF), because pain symptoms may limit children's ability to participate in their CF-related care and may reduce their overall well-being and quality of life. The aims of this study were to: 1) assess acute and chronic pain symptoms as reported by children with CF, and 2) examine the relationship between pain symptoms and disease severity as measured by percentage of forced expired volume in 1 sec (FEV1%). Forty-six children completed a self-report questionnaire assessing characteristics of chronic disease-related pain (frequency, intensity, duration, associated emotional upset, and location of pain). Children also rated their pain intensity associated with common CF-related procedures. The primary locations of pain reported were the abdominal/pelvic region, chest, and head/neck. Forty-six percent of the sample described pain occurring at least once per week. Most children reported their pain intensity as mild and of short duration. However, a small subgroup of children reported longer-lasting and moderately intense pain. Children with chest pain were found to be particularly at risk for experiencing more functional limitations and a significantly lower FEV1% compared to children without chest pain. The majority of children reported that nonpharmacological therapies (e.g., medication, rest, or distracting activities) provided some pain relief. Disease-related pain is common for children and adolescents with CF, suggesting that pain assessment should be a routine part of their clinical care. Further research is clearly needed to better understand the sources of pain and how best to provide relief.

Acute Disease↗
PubMed2005

The cell cycle associated protein, HTm4, is expressed in differentiating cells of the hematopoietic and central nervous system in mice.

HTm4 is a member of a newly defined family of human and murine proteins, the MS4 (membrane-spanning four) protein group, which has a distinctive four-transmembrane structure. MS4 protein functions include roles as cell surface signaling receptors and intracellular adapter proteins. We have previously demonstrated that HTm4 regulates the function of the KAP phosphatase, a key regulator of cell cycle progression. In humans, the expression of HTm4 is largely restricted to cells of the hematopoietic lineage, possibly reflecting a causal role for this molecule in differentiation/proliferation of hematopoietic lineage cells. In this study, we show that, like the human homologue, murine HTm4 is also predominantly a hematopoietic protein with distinctive expression patterns in developing murine embryos and in adult animals. In addition, we observed that murine HTm4 is highly expressed in the developing and adult murine nervous system, suggesting a previously unrecognized role in central and peripheral nervous system development.

Amino Acid Sequence↗
PubMed2004

A TRPV2-PKA signaling module for transduction of physical stimuli in mast cells.

Cutaneous mast cell responses to physical (thermal, mechanical, or osmotic) stimuli underlie the pathology of physical urticarias. In vitro experiments suggest that mast cells respond directly to these stimuli, implying that a signaling mechanism couples functional responses to physical inputs in mast cells. We asked whether transient receptor potential (vanilloid) (TRPV) cation channels were present and functionally coupled to signaling pathways in mast cells, since expression of this channel subfamily confers sensitivity to thermal, osmotic, and pressure inputs. Transcripts for a range of TRPVs were detected in mast cells, and we report the expression, surface localization, and oligomerization of TRPV2 protein subunits in these cells. We describe the functional coupling of TRPV2 protein to calcium fluxes and proinflammatory degranulation events in mast cells. In addition, we describe a novel protein kinase A (PKA)-dependent signaling module, containing PKA and a putative A kinase adapter protein, Acyl CoA binding domain protein (ACBD)3, that interacts with TRPV2 in mast cells. We propose that regulated phosphorylation by PKA may be a common pathway for TRPV modulation.

ATP-Binding Cassette Transporters↗
PubMed2004

RGA protein associates with a TRPV ion channel during biosynthesis and trafficking.

TRPV ion channels transduce a range of temperature stimuli. We proposed that analysis of the protein-protein interactions made by TRPV2 might give insight into the key issues surrounding this channel. These issues include the potential functional significance of TRPV2 in non-sensory tissues, the molecules involved in transducing its activation signal(s) and the mechanism by which its trafficking to the cell surface is regulated. Here we describe the interaction of TRPV2 channel with the RGA gene product. RGA is a four-transmembrane domain, intracellularly localized protein. RGA associates with TRPV2 in a rat mast cell line that is a native context for both proteins. The interaction between TRPV2 and RGA is transient and occurs intracellularly. RGA does not accompany TRPV2 to the cell surface. Formation of the TRPV2/RGA complex is dependent upon a cellular glycosylation event, suggesting that RGA may play a chaperone or targeting role for TRPV2 during the maturation of the ion channel protein. These data record a novel protein-protein interaction for TRPV2 and provide a foundation for future study of the potential regulatory contribution of RGA to TRPV2 function.

Animals↗
PubMed2004

A randomized, double-blind comparison study of EMLA and ELA-Max for topical anesthesia in children undergoing intravenous insertion.

BACKGROUND: Topical anesthetics may help reduce discomfort associated with procedures involving needle-puncture, such as intravenous (i.v.) insertions, in children. EMLA cream has become a common, noninvasive therapy for topical anesthesia in children. ELA-Max is a recently introduced topical anesthetic cream marketed as being as effective in producing topical anesthesia after a 30-min application as EMLA is after a 60-min application. The purpose of this research was to compare ELA-Max at 30 min with EMLA at 60 min for providing topical anesthesia for i.v. insertions in children. METHODS: Sixty children, ages 8-17 years, requiring an i.v. were randomized to receive either the 30 min application of ELA-Max (n = 30) or the 60 min application of EMLA (n = 30). Children rated any pain associated with the i.v. insertion using a 100-mm Visual Analog Scale (VAS). The anesthesiologist assessed the presence of blanching at the site and rated the difficulty of placing the i.v. RESULTS: There was no clinically or statistically significant difference in pain ratings (P = 0.87) between the ELA-Max (mean = 25.7) and the EMLA (mean = 26.8) groups. ELA-Max caused significantly (P = 0.04) less blanching than EMLA, however there was no difference in the anesthesiologists' rating of the difficulty of the i.v. placement between the groups (P = 0.73). CONCLUSION: Results from this study support the claim that a 30-min application of ELA-Max (with occlusion) is as effective as a 60-min application of EMLA (with occlusion) for producing topical anesthesia for i.v. insertion in children.

Administration, Topical↗
PubMed2003

Differential roles of CB1 and CB2 cannabinoid receptors in mast cells.

Cannabinoid modulation of immune responses is a pathological consequence of marijuana abuse and a potential outcome of therapeutic application of the drug. Moreover, endogenous cannabinoids are physiological immune regulators. In the present report, we describe alterations in gene transcription that occur after cannabinoid exposure in a mast cell line, RBL2H3. Cannabinoid exposure causes marked changes in the transcript levels for numerous genes, acting both independently of and in concert with immunoreceptor stimulation via Fc epsilon RI. In two mast cell lines, we observed mRNA and protein expression corresponding to both CB1 and CB2 cannabinoid receptor isoforms, contrary to the prevailing view that CB1 is restricted to the CNS. We show that coexpression of the two isoforms is not functionally redundant in mast cells. Analysis of signaling pathways downstream of cannabinoid application reveals that activation of extracellular signal-regulated kinase, AKT, and a selected subset of AKT targets is accomplished by CB2 ligands and nonselective CB1/CB2 agonists in mast cells. CB1 inhibition does not affect AKT or extracellular signal-regulated kinase activation by cannabinoids, indicating that CB2 is the predominant regulatory receptor for these kinases in this cell context. CB1 receptors are, however, functional in these mast cells, since they can contribute to suppression of secretory responses.

Animals↗
PubMed2003

Discrimination of intracellular calcium store subcompartments using TRPV1 (transient receptor potential channel, vanilloid subfamily member 1) release channel activity.

The store-operated calcium-release-activated calcium current, I (CRAC), is a major mechanism for calcium entry into non-excitable cells. I (CRAC) refills calcium stores and permits sustained calcium signalling. The relationship between inositol 1,4,5-trisphosphate receptor (InsP(3)R)-containing stores and I (CRAC) is not understood. A model of global InsP(3)R store depletion coupling with I (CRAC) activation may be simplistic, since intracellular stores are heterogeneous in their release and refilling activities. Here we use a ligand-gated calcium channel, TRPV1 (transient receptor potential channel, vanilloid subfamily member 1), as a new tool to probe store heterogeneity and define intracellular calcium compartments in a mast cell line. TRPV1 has activity as an intracellular release channel but does not mediate global calcium store depletion and does not invade a store coupled with I (CRAC). Intracellular TRPV1 localizes to a subset of the InsP(3)R-containing stores. TRPV1 sensitivity functionally subdivides the InsP(3)-sensitive store, as does heterogeneity in the sarcoplasmic/endoplasmic-reticulum Ca(2+)-ATPase isoforms responsible for store refilling. These results provide unequivocal evidence that a specific 'CRAC store' exists within the InsP(3)-releasable calcium stores and describe a novel methodology for manipulation of intracellular free calcium.

Animals↗
PubMed2003

Demographic and clinical characteristics of adolescents in Hawaii with obsessive-compulsive disorder.

BACKGROUND: A high prevalence rate of obsessive-compulsive disorder (OCD) among Hawaiian adolescents, particularly Native Hawaiians, has been reported. Because Native Hawaiian and other Polynesian youth are at an increased risk for rheumatic fever, caused by an autoimmune response to group A beta-hemolytic streptococci, we hypothesized that the genetic and environmental risk factors for streptococcal infections and their autoimmune sequelae potentially may be associated with the presence of OCD and may partially explain this high OCD prevalence. OBJECTIVE: To describe, among the adolescents in Hawaii diagnosed as having OCD through a previous study, OCD prevalence by ethnicity, household crowding and other measures of socioeconomic status, various measures of physical health and health-seeking behavior, and comorbid psychopathologic features. DESIGN: Six hundred nineteen adolescents from 5 high schools in the state of Hawaii were interviewed from April 15, 1993, to May 7, 1996. Interview instruments included the Diagnostic Interview Schedule for Children and other measurements of psychopathology. Obsessive-compulsive disorder diagnoses, based on current and past 6-month symptoms elicited via structured interview of the adolescents, were reported. RESULTS: Relative to other ethnicities, Native Hawaiians had a 2-fold higher risk (odds ratio = 2.03) for OCD. Degree of Polynesian ancestry correlated positively with OCD prevalence. Obsessive-compulsive disorder prevalence also correlated positively with crowding in the household; measures of physical illness; and measures of depression, anxiety, aggression, and illicit substance use. CONCLUSIONS: The characteristics of OCD in this sample suggest the need to consider the possibility of a streptococcal origin and the need for further studies to clarify the genetic and environmental risk factors for OCD in Hawaiian and other Polynesian youth.

Adolescent↗
PubMed2003

Including culturally diverse samples in health research: a case study of an urban trial of social support.

OBJECTIVES: To describe the recruitment procedures used in a study of Social Support and Family Health carried out in a disadvantaged urban area of the UK in 1999-2001; to consider the impact of using inclusive recruitment procedures on the final research sample and implications for the conduct of the research and data obtained. DESIGN: Face-to-face recruitment of eligible women, using interpreters where necessary, to a randomized controlled trial of two alternative strategies for providing support to women with infants. RESULTS: Of the 1,263 women eligible to enter the trial, 731 were successfully recruited. Forty-five languages other than English were spoken by eligible women; 14% needed an interpreter for the recruitment visit, and a further 30% spoke English as a second language. Inclusive recruitment practices added significant costs, resulted in a study sample with a different social profile from the sample that would have been achieved without these, and challenged some of the assumptions underlying the model of informed consent commonly used in much health services research. CONCLUSION: Procedures can be developed for recruiting people with diverse cultural backgrounds to take part in research. This helps to address the issue of possible bias in generalizing research findings by increasing external validity, and respects the ethic that everyone should have the right to be eligible for inclusion in research.

Cultural Diversity↗
PubMed1998

Evaluating parent support initiatives: lessons from two case studies.

This study describes the characteristics of clients referred to two UK parent support initiatives - Newpin and Home-Start - and documents key aspects of the referral process and clients' responses to the help provided. Data were collected from referral records on 214 families referred during 1992 to four Newpin centres and 349 families referred between April 1994 and March 1995 to four Home-Start schemes. Families were sent questionnaires. Qualitative interview data were collected from a sub-sample of families and from staff and referrers in the Newpin study; volunteers and referrers completed questionnaires in the Home-Start study. Socially disadvantaged families were less likely to return the study questionnaires. The kinds of families and problems referred to the two organizations were very similar. Mothers' loneliness and low emotional well-being were the main reasons for referral; children at risk represented a small part of the caseload. Both Newpin and Home-Start respondents had low levels of support from family and friends. Most referrals were made by health visitors, and there was a significant problem of non use among referred families. Most users of Newpin and Home-Start were enthusiastic about the help provided. Common difficulties in family life, such as poverty, stress and low social support, make up an increasing part of the workload of health professionals and social workers, and of voluntary sector initiatives for supporting parents. This study raises questions about the claims such initiatives may make about their effectiveness in reaching and providing help to 'at risk' families. Further evaluation of such schemes is needed to provide a sound evidence-base for policy and purchasing decisions.

Journal Article↗