December 2004 INFECTION IMMUNITY INFLAMMATION www.cardiff.ac.uk/medicine/research/irg/i3.html I3-IRG Newsletter Welcome to the 2nd edition of the I3-IRG CHAIRMAN’S THOUGHTS newsletter. Its aim is to keep you informed of IRG activities as well as to
Reflecting on the first full year of this IRG, one of the satisfying achievements has been the success of the
foster inter-disciplinarity, collabo- ration
various scientific meetings that have been organised to encourage discussions and collaborations between
and information exchange. With this in
groups in Cardiff. These have taken the form of ‘getting-to-know-what’ s-going-on meetings’ organised
mind this issue (and future ones) will
by different research groupings, technology-based meetings to highlight current resources, and the annual
include features on different
two-day event at Gregynog. We plan to continue with these meetings over the coming year. The first will
sections/research groups to increase
be on the theme of “in vivo”, and is being organised by Anwen Williams and Nick Topley. Suggestions for
awareness of their ongoing activities and
additional events are always welcomed, and any ideas should be conveyed to a member of the Steering
to potentially develop new research co- operation. In line with the development
Regarding the Steering Committee, there will soon be a call for nominations and an election of members.
of the news-letter the new I3-IRG web
This committee serves an important function in formulating policy, and in coordinating the action
site will be unveiled in January this will
required to allow the activities of the I3 IRG to succeed. Please give consideration to whether you could
now be seen as a direct link from the
give some of your time and energy to serve on this committee.
University home page (www.cardiff.
One of the issues addressed by the IRG Steering Committee is that of PhD studentships. The outstanding
ac.uk/medicine/research/irg/i3.htm) and
sweep of the prizes by students from this IRG at the WCM Prograduate Research Day in November, is
will be gradually integrated into the
testimony to the quality of our students. It is therefore a concern that no studentships are available to us
main site.
from the University this year. Coupled with the reorganisation within the MRC, which has effectively
We welcome your views on the format
reduced the number of their studentships, we are likely to undergo a marked decline in the number of
and content of the newsletter and thank
students able to receive the excellent training we can offer. As one step to addressing this problem, the
those who have contributed copy to this
Steering Committee proposes to use a major part of our financial resources to sponsor its own
studentship this year. However, we do not have sufficient funds to do repeat this initiative, and every
Merry Christmas and best wishes for a
effort must be made to persuade the WCM of the seriousness of this issue.
productive 2005 Nick Topley ([email protected]) PRIMARY CARE RESEARCH INTO COMMON INFECTIONS:AN OPPORTUNITY FOR I3-IRG SCIENTISTS DOMINATE AWARDS AT SYNERGY BETWEEN THE CHSR AND I3 IRG? INTERNATIONAL CYTOKINE SOCIETY MEETING
About 90% of consultations in the NHS take
Prestigious awards were recently presented to members
controlled trial in general practice evaluating
of the I3 IRG at the recent Cytokines in Cancer and Im-
intranasal sodium cromoglicate for suspected
reason is infection and inflammation. The
munity meeting held jointly by the International Cyto-
acute viral upper respiratory tract infections
Centre for Health Sciences (CHS) IRG has
kine Society (ICS) and the International Society for In-
in children. From this work, we were also
‘common infections in primary care’ as one
terferon and Cytokine Research (ISICR) held in Puerto
able to describe the natural history of the
of its research themes Cardiff has a long
condition and clinical predictors of poor
tradition of research on common infections
in primary care. In the 1970Õs, Nigel Stott
researchers form several other departments
published one of the first major randomised
antibiotic treatment offers little or no
(Epidemiology, Statistics and Public Health)
benefit to adult patients with bronchitis.
is studying the aetiology of antimicrobial
This landmark study had a major impact on
resistance in urinary tract infections in
antibiotic prescribing decisions. Another
study, this time on children with winter
upper respiratory tract infections, showed
prescribing in general practice, linking these
prescribing by GPs was not associated with
data is allowing us to explore the association
differences in outcome. More recently, we
have focussed on using qualitative research
antimicrobial resistance. A similar database
methods to better understand the complex
linking prescribing and resistance in patents
prescribing. I am currently focussing on GPs
Together with colleagues form Maastricht
decisions about which antibiotic to prescribe, University, we have obtained funding from
and to understand the great variation in the
the Dutch MRC for a trial on the use of C -
use of broad spectrum antibiotics, especially reactive protein in the management of
fluroquinolones. As antibiotic prescribing
coughing adults in primary care. Smaller,
ongoing studies include the presentation of
clinicians are worried that complications
TB in primary care and the empirical use of
form common infections will increase. We
antibiotics for urinary tract infections.We are Germany) were jointly presented
are using large databases to explore this
also part of a bid for EU funding to establish
the inflammatory consequences of IL-6 trans-signalling.
INFECTION IMMUNITY INFLAMMATION PRIMARY CARE RESEARCH (CONTD) I3 IRG STUDENTS DOMINATE THE AWARDS AT THE POSTGRADUATE RESEARCH DAY
a Network of Excellence for enhancing management of lower respiratory
tract infections in primary care. If successful, Cardiff will lead the clinical
The 19th annual Postgrad Day was held on Friday 19th November at the
platform which will involve community-based general practice research
Wales College of Medicine. After an opening address from the Vice
groupsacross 12 countries. Innovations in genomics, microbiological
Chancellor, Professor Steve Tomlinson more than 70 higher degree
techniques and clinical and behavioural aspects be developed and
students from the School of Medicine and, for the first time from
evaluated. Large randomised controlled trials and will follow etiological
Pharmacy, Biosciences and Optometry, presented their research as oral
Other studies that await funding decisions include a trial on the
This years keynote speakers were Professor Steve O’Rahilly who spoke
management of children with respiratory tract infections, and one on
about diabetes and obesity and the genetics that govern it and Professor
Steve Jones, (geneticist, broadcaster and Daily Telegraph columnist)
Communication and behavioural sciences are key to developing
who gave an entertaining account of the parasitic nature of men and
interventions aimed at effective clinician and patient behaviour change.
Apart from primary research, we have contributed to several systematic
As always, the day was extremely successful with an extremely high
reviews, for example, on the management of otitis media with effusion,
standard of presentation. The organisers are grateful to those companies
that provided generous sponsorship and to the judges for their work in
Not everyone in the I3-IRG will know about this research area, the hope is
adjudicating on the oral and poster presentations.
to spark possible ideas for inter-IRG collaboration in the arena of infection. Ivan Wall, Postgraduate Society
It may just be that you are aware of a new idea or technology for diagnosis
or treatment of common infections that may just be crying out for
Oral presentation winners:
evaluation in primary care. Such an initiative could be the main focus of a
Stefan Siebert
community based trial, or linked to studies already planned, for example
Poster presentation winners:
our RCT involving CRP in coughing adults. It would be a real achievement if
Catherine Wilson
we could turn the vision of joined-up research (‘from molecule to patient
Butler CC, Rollnick S, Maggs Rapport F, Pill RM, Stott NCH. Under- Melanie Armstrong
standing the culture of prescribing: A qualitative study of general practitio-
Karolina Taylor
ners' and patients’ perceptions of antibiotics for sore throats. BMJ
Butler CC, Rollnick S, Tapper-Jones L, Kinnersley P, Houston H. Melody Liles
Communicating about expected course and re-consultation for respiratory
tract infections in children: an exploratory study. British Journal of General
Jayne Chamberlain Chris Butler Professor of Primary Care Medicine ([email protected]) FOCUS ON I3-IRG RESEARCH: RESEARCH IN MEDICAL MICROBIOLOGY FOCUSES ON MECHANISMS OF MICROBIAL PATHOGENESIS
The major research theme in Medical cepacia complex and P. aeruginosa, we are
Invasive fungal infections are a growing concern
Microbiology is ‘microbial pathogenesis’ and studying the receptorsand signalling pathways
in many groups of hospital patients. The
covers pathogenic mechanisms of bacterial, viral utilised by LPS from these species (Ryley Group). molecular diagnosis and pathogenesis of Candida
and fungal pathogens. Microbial pathogenesis is The recent identification of highly transmissible
and Aspergillus infections and the development
an outcome of the interaction between a micro- and virulent strains of these organisms has added of antifungal agents are important research
organism and a host – damage to the host can to the importance of this work. These studies
result from microbial factors and/or the host have also suggested potential alternative
response. We are concerned both with the receptors and signalling pathways for LPS and
research in microbial pathogenesis is the
virulence factors used by the microbes and the other bacterial cell wall molecules and the PAF
translation of the research into clinical
receptor is being studied in this regard (Tonks
applications and we have close collaborations
An important and productive research area is the group).
with the Wales NPHS to further this work.
study of bacterial lipopolysaccharide (LPS) as a The department has expertise in anaerobic
Utilising genomics to provide improved molecular
virulence factor in infectious disease (Jackson bacterial infections through the NPHS anaerobe
diagnoses for a range of infections has been a
Group). Within this area, we have been reference laboratory (Brazier group). A current
significant success of our clinically-applied
investigating the regulation of innate responses area of collaboration with this group is the role
to LPS, in particular with respect to the of LPS in the pathogenesis of severe infections
development of sepsis. In collaboration with with Fusobacterium necrophorum.
techniques (EPR oximetry; with Philip James,
Professor John Harwood (Biosciences) we have The molecular mechanisms of poxvirus
Cardiovascular Sciences) that allow measurement
identified a lipid metabolizing enzyme pathogenesis (Bugert Group) is the major
of critical molecules (NO, O2) at specific sites in
(lysophosphatidylcholine acyltransferase) in interest of the virology section. Poxviruses
experimental models of infection has also been a
leukocytes that can regulate inflammatory encode immune evasive factors and many
productive area of our research in sepsis and led
responses to LPS via effects on leukocyte poxvirus proteins are homologues of cellular
to successful international collaborations (Hal
membrane microdomains. We are currently gene products, making them suitable model
cloning and expressing this enzyme to further systems for studying host-pathogen
Currently we are initiating collaborations with
investigate its role in LPS responses. This work interactions. The immune evasive mechanisms
microbiologists at the Swansea Clinical School
and related studies on LPS-leukocyte mediated by the mc080 MHC class I homolog and (Dietrich Mack and Stephen Kelly) and
interactions, have also identified a potential role mc161R of the Molluscum Contagiosum Virus
Biosciences at Cardiff (Andrew Weightman and
for certain lipids as immuno-modulators and are (MCV) are important areas of current research.
Esh Mahenthiralingam) to use bacterial genomics
identifying the molecular mechanisms by which In addition, we are producing recombinant
to identify candidate virulence factors and
pulmonary surfactant lipids can down-regulate poxviruses expressing proteins of other viruses
elucidate their mechanisms of pathogenesis.
inflammatory responses to LPS which may have for evaluation in animal model systems and
Ultimately, increased knowledge gained from
therapeutic potential in infectious/inflammatory ultimately as candidate vaccines. Together with
studying mechanisms of microbial pathogenesis
Dr. Arwyn Jones (School of Pharmacy), we are
will hopefully lead to the development of novel
Recent work has highlighted LPS as an important investigating the interaction of viruses with host antimicrobial strategies.
virulence factor in lung infections with B.
Simon K. Jackson, Research Director, Medical
INFECTION IMMUNITY INFLAMMATION FOCUS ON I3-IRG “HOT HITS” RESEARCH PUBLICATIONS 'HPV RESEARCH UPDATE' Mizuno M, Harris CL, Johnson PM, Morgan BP. Rat membrane cofactor protein (MCP; CD46) is expressed only in the acrosome of
developing and mature spermatozoa and mediates binding to immobilized activated C3. Biol Reprod. 2004 Oct;71(4):1374-83. This paper described the analysis using newly derived monoclonal antibodies of the unusual distribution of the membrane-bound comple-Williams JD, Topley N, Craig KJ, Mackenzie RK, Pischetsrieder M, Lage C, Passlick-Deetjen J. The Euro-Balance trial: the effect of
a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane. Kidney Int 66: 408-418, 2004. Results of a major new trial of more biocompatible peritoneal dialysis solutions, demonstrate evidence of membrane preservation in PD pa-Sathish JG, Walters J, Luo JC, Johnson KG, Leroy FG, Brennan P, Kim KP, Gygi, SP, Neel BG, Matthews RJ. CD22 is a functional
ligand for SH2 domain-containing protein-tyrosine phosphatase-1 in primary T cells. J Biol Chem. 2004 Nov 12;279(46):47783-91.
Fielding CA, Siebert S, Rowe M, Brennan P Analysis of human tumour necrosis factor receptor 1 dominant-negative mutants reveals
a major region controlling cell surface expression. FEBS Lett 2004;570(1-3):138-42. Identification of a region in the cytoplasmic c-terminus that regulates TNF-R1 cell surface expression. Morgan BP, Griffiths M, Khanom H, Taylor SM, Neal JW. Blockade of the C5a receptor fails to protect against experimental autoim- mune encephalomyelitis in rats. Clin Exp Immunol. 2004 Dec;138(3):430-8 Recently we showed that the terminal pathway of com- plement is essential for demyelination in the the rat models of MS, EAE and ADEAE. Here we used a peptide inhibitor of the C5a receptor to investigate whether this extremely pro-inflammatory product of complement activation was responsible for the ob-served complement-dependent inflammation. Marcus J. Coffey, Barbara Coles, Matthew Locke, Alexandra Bermudez-Fajardo, P. Claire Williams, Gavin E. Jarvis & Valerie B. O'Donnell Interactions of 12-lipoxygenase with phospholipase A2 isoforms following platelet activation through the glycoprotein VI
collagen receptor (2004). FEBS Letters 8 October 2004 Vol. 576, No. 1. This paper concentrated on looking at the enzymes in plate-lets that provide the arachidonic acid substrate for the lipoxygenase. Ayub K, Hallett MB.The mitochondrial ADPR link between Ca2+ store release and Ca2+ influx channel opening in immune cells.
FASEB J. 2004 Sep;18(12):1335-8. In this paper, evidence is presented for a link between the release of ADPR from mitochondria and the opening of Ca2+ permeable LTRCPC2 channels in the membrane of immune cells, giving a novel potential mechanism for Baalasubramanian S, Harris CL, Donev RM, Mizuno M, Omidvar N, Song WC, Morgan BP. CD59a is the primary regulator of mem-
brane attack complex assembly in the mouse. J Immunol. 2004 Sep 15;173(6) :3684-92. This paper set out to resolve a controversy regarding the distribution and functional roles of these two forms of CD59. Harris CL, Abbott RJ, Smith RA, Morgan BP, Lea SM. Molecular dissection of interactions between components of the alternative
pathway of complement and decay accelerating factor (CD55). J Biol Chem. 2004 Nov 9. This paper describes a novel approach to investigating the assembly and decay of the enzymes of the complement activation pathway using surface plasmon resonance (BIACore) to measure in real time the complex interactions occurring. Hill SC, Youde SJ , Man S, Teale GR, Baxendale A, Hislop A, Davies CC, Luesley DM, Blom AM, Rickinson AB, Young LS and Eliopoulos AG Activation of CD40 in cervical carcinoma cells facilitates cytotoxic T lymphocyte responses and augments chemother-
apy-induced apoptosis. (2004). Journal of Immunology in press. Data suggests novel method to overcome immune evasion and resis-tance to chemotherapy in cervical cancer. Youde S, McCarthy C, Thomas K, Smith K, and Man S. Cross-typic specificity and immunotherapeutic potential of a human HPV16 E7
specific CTL line (2004) International Journal of Cancer in press. First demonstration that HPV specific CTL can cross-react between different HPV types. Siebert S, Amos N, Fielding CA, Wang E, Aksentijevich I, Williams BD and Brennan P. Reduced tumour necrosis factor signaling in
primary human fibroblasts containing a tumour necrosis factor receptor superfamily 1A (TNFRSF1A) mutant" Arthritis & Rheumatism
in press. Using patient derived material, this study, jointly performed by Rheumatology and Infection & Immunity, has identified a functional defect in TNFR1 signalling. Our work suggests that reduced TNFR1 signalling and apoptosis may explain this syndrome. Wellcome Trust Equipment Grant + SRIF2 “LC/ESI/MS/MS system (mass spectrometry) for development of lipidomics research“ £413,090 Dr Valerie O'Donnell, Professor John Harwood and collaborators (Brennan, Hallett, Lewis). Acquisition of high-sensitivity MS for lipid analysis in Cardiff will enable accurate quantitation and structural analysis of multiple lipids in small cells and tissue samples (e.g. 1 million cells or less). We aim for this instrument to become a central resource for lipid research in Cardiff. Our primary use for this instrument will be profiling of lipid signaling mediators (e.g. PAF, eicosanoids, leukotrienes, ceramide, phos-phoinositides, ceramides, etc) in vascular and inflammatory diseases. Anyone interested in using these facilities should contact Val
O' Donnell (([email protected]) for further information.
FUTURE I3 IRG EVENTS SITUATIONS VACANT GREGYNOG 2005 : RESEARCH ASSISTANT/POST DOCTORAL RESEARCHER Salary £19,460 - £29,128
Maximum starting salary £25,699. Fixed Term 3 Years funded by The Well-
come Trust. A Research Assistant or Post Doctoral Fellow is required for
operating and maintaining a newly purchased tandem mass spectrometer for
analysis of lipid signalling mediators in inflammation and vascular disease.
Specific projects will include analysis of enzymatically generated oxidised
STEERING COMMITTEE
lipids (e.g. prostaglandins, lipoxygenase metabolites, nitrated lipids) in mod-
Chairperson
els of hypertension, arthritis and peritonitis. The person will be responsible
Committee
for providing mass spectrometry technical support to others within and out-
side the group, and will be responsible for their own project (s) as appropri-
Secretary
ate. Full training will be given, but a background in mass spectrometry would Nicholas Topley:
be highly advantageous. For informal enquiries, contact Dr Valerie O'Donnell [email protected]
([email protected]), phone 029 2074 8447
Treasurer OST DOCTORAL RESEARCH FELLOW IN HPV INFECTION (£19,460 - £29,128)
An exciting opportunity has arisen for a post-doctoral research fellow to join
Meetings Organiser Zsuzsanna.Tabi@
the HPV molecular diagnostic laboratory, Department of Obstetrics & Gynae-
cology, Wales College of Medicine, Cardiff University. A highly motivated
and flexible individual is sought to work alongside the clinical team investi-
Post Doc Rep/
gating HPV infection in lower genital tract neoplasia. The HPV team is cur-
RACD Contact
rently developing prognostic markers for HPV infection as well as assessing
HPV response to novel therapies. The successful candidate will be expected [email protected][email protected]
to support the running of the HPV laboratories, the characterisation of HPV
Web Site: Representative
infection and the development of prognostic markers. Informal enquires only
to Professor A Fiander, Tel No 029 20743235.
International Journal of Pharmaceutics 309 (2006) 199–2071. Properties and in vitro/in vivo behavior of acyclovirYiguang Jin , Li Tong , Ping Ai , Miao Li , Xinpu Hou a Department of Pharmaceutical Chemistry, Beijing Institute of Radiation Medicine, Beijing 100850, PR China b Department of Physical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR Chi
Alerting business to threats from fraud and corporate crime Be wary of ‘jack of all trades’ online commodity traders says FIBoil, diesel, petrol, coal and cement. FBI, ICC and Interpol if a ‘not real’used to add credibility to the deal. In This Issue of CCI and after “checking with guys inthe UK” was virtually asked what COMMERCIAL CRIME CORRUPTION CYBERCRIME securit