Royal Hobart Hospital Research Foundation Incorporated

Royal Hobart Hospital ResearchFoundation Incorporated2002 ANNUAL REPORT

What is the ResearchFoundation?The Royal Hobart Hospital ResearchFoundation Inc. is an independent, privateorganisation which was established topromote and fund medical, healthcareand scientific research. The Foundationwas registered as an incorporated bodyin November 1997, and is administeredby a voluntary Board of Management drawnfrom the medical, business and generalcommunities.The Royal Hobart Hospital Research AdvisoryCommittee, comprising experiencedresearchers, undertakes the evaluation ofapplications to the Foundation for researchgrants, making recommendations onfunding based on independent assessments.Significant effort is made to ensure thatresearch undertaken is of the highestquality, uses sound medical or scientifictechniques and will bring benefits to thehealth and well-being of the patients ofthe Hospital and the people of Tasmania.The Foundation relies on the corporateand general communities for itsfundraising, which includes functions,statewide raffles, bequests and legacies,and a pay deduction scheme. In orderto maximise funding for research, theFoundation maintains a small, cost-efficientsecretariat of two staff, our ExecutiveDirector and Administrative Officer.Inside the 2002 annualreportThe year in review:pages 1 – 4Financial statement:page 5The Research Report, 1998 – 2002:pages 6 – 26Corporate information and oursponsors:back pageOur mission?• To resource and maintain a significantcapital base to enable the maintenanceand advancement of an internationalstandard of medical, scientific andhealthcare research in Tasmania.• To involve all relevant parties in debate,discussion and sponsorship to developand support an active locally-basedresearch program.1

1Chairperson’s reportOn behalf of the Board of Management of the Royal HobartHospital Research Foundation Inc. I am delighted to presentthe Chairperson’s report for the year ended 31 December 2002.The year 2002 has been one of major fundraising and researchactivity, with the profile and reputation of the ResearchFoundation now well established in the Tasmanian community.We have completed another full year of fundraising activities,as well as allocating close to $300,000 in medical and healthcareresearch in Tasmania. This brings to more than $1 million theamount made available to researchers by the Foundationin its first five years, helping to strengthen the medical researchinfrastructure of the Hospital and the University’s Clinical School,and resourcing high-quality, local medical research for thebenefit of all Tasmanians.The success of the Foundation’s fundraising, and the supportof Tasmanians throughout the year, reflect the standing of theFoundation in its community, and the developing understandingof the role played by local medical research in improvinghealthcare, creating long-term employment for our universitygraduates, and continuing to attract top quality healthprofessionals to work in the State’s health system.On behalf of the Board of Management and staff, I take thisopportunity to thank all our supporters for their generous efforts.Our balance sheet for the year ended 31 December 2002 detailsa net asset base of $741,797, and the Foundation’s Board ofManagement is determined to continue to build upon this tostrengthen and grow our capital funds.During the year in report, our former Administrative Officer,Natalie Neilson, moved to another position and we thankNatalie for her talented support, and wish her well for the future.As a result, Natasha Beveridge has joined our staff team of two.The Board would like to recognise the hard work and continuingcommitment of our Executive Director, Tony Reidy, andAdministration Officer, Natasha Beveridge, in working towardsthe achievement of the Foundation’s ambitious goals.I also place on record my thanks to my colleagues on the Boardof Management for their excellent voluntary contributions duringthe year and, in particular, my appreciation for the activesupport of the Foundation provided by the Hospital’s ChiefExecutive, Pat Martin, who left that position at the end of 2002.It is also important to remember that we could not have achievedour successes this year in fundraising and medical researchwithout the support of our many generous corporate andcommunity sponsors, to whom we owe a debt of gratitude.The Research Foundation looks forward to the excitingchallenges ahead as we continue to work towards improvedhealthcare for Tasmanians through locally-based, internationalstandardresearch.Ted HardnerChairpersonThe Foundation’s Boardat 31 December 20021. Ted Hardner (Chairperson)Retired businessman2. Elizabeth Thomas (Deputy Chair)Chief Executive OfficerThe Public Trustee3. David Catchpole (Treasurer)Chairman, Shadforths Ltd4. Erika WylieHobart Private Hospital/Mayne Health5. Pat J. MartinChief Executive OfficerRoyal Hobart Hospital6. Professor H Konrad MullerHead of Pathology;University of TasmaniaAssociate Dean of Research7. Helen DickinsonChair, Blundstone Pty Ltd8. Professor Ray LowenthalDirector of Medical OncologyRoyal Hobart Hospital;Clinical Professor, Universityof Tasmania9. Dr Anne BrandDirector, Hospitals & AmbulanceService, Dept of Health & HumanServices10. Ronald T. Banks AMHobart businessman11. Professor Haydn WaltersHead of Discipline of Medicine,University of Tasmania;Clinical Chief of Medicine,Royal Hobart Hospital12. Tony Reidy (Executive Director)Public Officer & SecretaryPatron: The Hon. Sir Max Bingham QC23456789101112

Exciting year of localresearch fundingDuring 2002 the Research Foundation awardedclose to $300,000 in research grants.Major Grants were awarded for studiesin the areas of leukaemia, schizophrenia,epilepsy, the link of bacteria to humaninfections, immunosuppresive proteins,glaucoma, anti-clotting drugs, congenitalcataracts, multiple sclerosis, decompressionstress for salmon industry divers, andresearch on glycoproteins.Phase two of a two-year study on theimmunopathology of asthma was alsofunded, as was the second year of a threeyearinvestigation into Parkinson’s disease.The Parkinson’s research was made possiblethrough a bequest in the will of a Tasmanianbusinessman, Bevis Thomas, who died ofthe disease in 1991.The Research Foundation is in the processof funding another significant grantsprogram as this annual report goes to print– made possible through the success of itsfundraising activities during 2002.For a full list of the research grants awarded bythe Foundation, including 2003, please visitour web site at www.rhhresearch.tas.gov.auThe Foundation’s backboneis made of ‘Cherries’!With a staff of only two, the ResearchFoundation’s ambitious fundraisingprograms would simply not be possiblewithout the support of so many wonderfulpeople and, in particular, our volunteerswho assist in many different ways,especially with our fundraising campaignsand community functions.And at the very core of that support are theRoyal Hobart Hospital Cherry Volunteers –a group of community-minded women andmen who are almost an extension of theFoundation office in their assistance withmail-outs, the posting of our Questnewsletter, and the preparation for andstaging of our major functions.The ‘Cherries’ are capably led by the alwaysenergetic and especially well-organisedWendy Petterd and Mary Gates. Wendy, Maryand all the Cherry Volunteers – take a bow!Big December Breakfastgets even bigger!The Research Foundation’s Motors’ Breakfastseries (MBS) was another resounding successduring the year.The series saw near-capacity audiencesat its regular functions, close to 400 at theJuly ‘Christmas in Winter’ breakfast, anda record-breaking 1,015 at the Big DecemberBreakfast!The series is sponsored by Motors Pty Ltdand the Hotel Grand Chancellor, with eachevent also co-sponsored by a generousTasmanian business.The icing on the cake – the Big DecemberBreakfast, with the very talented andenergetic Robyn Archer (pictured above)as guest speaker – not only broke allTasmanian records for attendance at aformal fundraiser, but also saw supporterson the morning carrying away tens ofthousands of dollars worth of lucky envelopeand door prizes thanks to the supportof over 100 prize sponsors.MBS in 2002 has resulted in a significantboost to our research funds, and greatlyassisted in promoting the vital cause ofmedical and healthcare research in Tasmania.3Leaders of the gang: Wendy Petterd (right)and Mary Gates.

Royal Hobart Hospital Research Foundation Inc.Audited Statement of Financial Position as at 31 December 20022002 2001$ $Accumulated FundsOpening Accumulated Funds 570,473 603,219Current Year Surplus/(Deficit) 171,324 (32,746)Total Accumulated Funds 741,797 570,473Current AssetsCash 604,299 399,130Barter Card 3,674 1,048Qantas Voucher 2,493 1,789Receivables 6,718 13,514GST Recoverable 23,947 16,667Investments 227,713 240,142Total Current Assets 868,844 672,290Non Current AssetsProperty and Equipment 5,045 4,278Less Accumulated Depreciation (3,006) 2,039 (1,737) 2,541Motor Vehicle 29,989 21,327Less Accumulated Depreciation (5,176) 24,813 (11,992) 9,335Total Non Current Assets 26,852 11,876Total Assets 895,696 684,166Current LiabilitiesPayables 11,043 8,654Research Project Payables 132,498 83,092GST Payable 4,055 118Provisions 6,303 6,975Asset Purchase Loan:Gross Instalments - 3,454Less Charges Not Yet Due - - (1,189) 2,265Total Current Liabilities 153,899 101,104Non Current LiabilitiesAsset Purchase Loan:Gross Instalments - 13,454Less Charges Not Yet Due - - (865) 12,589Total Non Current Liabilities - 12,589Total Liabilities 153,899 113,693Net Assets 741,797 570,4735

The Research ReportThe first grant round for the Royal Hobart Hospital Research Foundation was in 1998, about six months afterthe organisation was formed.By the end of 2002, the Foundation had funded and committed over $1 million for local medical, scientificand healthcare research.The research funded is determined after a stringent peer review process conducted by the Royal HobartHospital Research Advisory Committee, and only projects of excellence are selected.The following pages provide an update on the progress of the majority of those research projects, andthe Research Foundation’s 2003 annual report will cover the remainder of the investigations, as well asreporting achievements on the major projects funded during that year.

1998A study of the epidemiologyof allergy to jack jumperant stings. A descriptive,retrospective analysis ofcases in Southern Tasmania– total $69,000This project team’s total funding was receivedbetween 1999 and 2001, and comprised $32,000directly from the Foundation, $22,000 from thePark family and $15,000 from the former ClarenceJaycees.The project team membersDr Simon Brown, Emergency Physician,Royal Hobart HospitalMichael Wiese, Specialist Pharmacist,Royal Hobart HospitalDr Robert Heddle, Director of Immunology,Flinders Medical CentreDr Konrad Blackman, Emergency Physician,Royal Hobart HospitalVikki Stenlake, Research Nurse,Royal Hobart HospitalDr Rod Franks, Emergency Physician,Royal Hobart HospitalDr Brian Baldo, Molecular Immunologist, retired;previously of NSL Health Ltd MelbourneDr Greg Woods, Senior Lecturer, Disciplineof Pathology, University of Tasmania, HobartMatilda Haas, Science Honours student, Universityof Tasmania, HobartAndrew Black, Medical Honours student,University of Tasmania, HobartAnand Parameswaran, Medical Honours student,University of Tasmania, HobartThe aim of the researchThe principal aim of these projects was to outlinethe epidemiology and natural history of the jackjumper ant (Myrmecia pilosula) venom anaphylaxisin Tasmania and develop an effective treatment(venom immunotherapy) for people with lifethreateningallergy. A secondary aim was toinvestigate diagnostic approaches to insect allergyand the mechanisms underlying the clinical effectof immunotherapy.Achievements to dateThe team has clearly demonstrated that jackjumper ant venom allergy is a major problem inTasmania, affecting 2.7% of the population, with1% of the population having suffered a lifethreateningreaction when stung. A staggering12% of the Tasmanian population is stung by jackjumpers every year, and the risks of developingjack jumper venom allergy, and having a lifethreateningreaction, both increase almost threefoldwith age>35 years. During the team’s studyfollow-up period, people with a history of allergicreactions had a 70% risk of having a furtherreaction if they received another sting – anexceptionally high figure (compared with 25-50%risks quoted for wasp and bee sting allergy).Dr Simon Brown – ’Antman‘Major advances have been made in the extractionof venom from jack jumpers by electricalstimulation (which allows us to return them totheir nest so that they can be milked again later),which will enable us to produce large amountsof venom extract. This method supersedes earlier(and much more expensive) methods of venomextract production, which involved dissecting thevenom sac from each ant by hand under adissecting microscope.We have completed our clinical trial of venomimmunotherapy, which involved 68 highlyallergic volunteers. The results of this researchrepresent a major step forward in the treatmentof ant venom allergy. Other studies on themechanisms by which immunotherapy works,clinical aspects of life-threatening reactions, anddiagnostic approaches to insect sting allergy arein the process of being completed.Additional funding obtainedInitial funding by the Research Foundationwas a key element to the team going on to geta major grant (the Dick Buttfield MemorialScholarship – $150,000, awarded to Dr SimonBrown) and industry sponsorship ($200,000)to see the clinical trial through to completion.Publications to the end of 20021. Brown SG, Wu QX, Kelsall GR, Heddle RJ andBaldo BA. Fatal anaphylaxis following jackjumper ant sting in southern Tasmania.Med J Aust 2001; 175(11-12): 644-7.2. Brown SG, Franks RW, Baldo BA and Heddle RJ.Prevalence, severity, and natural history ofjack jumper ant venom allergy in Tasmania.J Allergy Clin Immunol 2003; 111(1): 187-92.An evaluation of the lowdose Synacthen test forthe detection of secondaryadrenal deficiency – $7,600The project team membersDr John Burgess, Director, EndocrinologyLaboratory, Royal Hobart HospitalMs T Lawrence, Dr T Greenaway, Dr V Parameswaran7In 1998, the Foundation’s inaugural ExecutiveDirector, Gary Knight (right), accepted a generousdonation from the then Blundstone CEO, Tony Stacey.

The aim of the researchThe aim of this project was to determine thedynamics of adrenocortical response to a 1mcgintravenous dose of Synacthen in both healthand disease. In addition the research sought todetermine the optimal method of applicationand interpretation of the 1mcg Synacthen test forassessing HPA axis function in a clinical setting.Achievements to dateInitial work in relation to this project wasundertaken during 1998. Seventy-eightindividuals were assessed for adrenal responsefollowing 1mcg of intravenous Synacthen. Thiswork resulted in the preparation of two Honourstheses, one for Ms Torey Lawrence (who receivedFirst Class Honours) and second for Mr DavidWright (who received Second Class Honours) forsubsequent work undertaken on the data in 1999.This research allowed normative data to beestablished for the 1mcg Synacthen test as wellas a usable protocol for patient assessment at theRoyal Hobart Hospital. As a consequence of thisresearch, protocols for patient management andinvestigation at the Royal Hobart Hospital weremodified. A large number of patients who wouldotherwise require the potentially dangerous insulintolerance test have been spared this investigation,instead undergoing the safer and simpler 1mcgSynacthen test to assess HPA axis function.Publications to the end of 2002Honours theses as detailed above.The role of immatureLangerhans cells in thedevelopment of the skinimmune system and theirpotency as immunomodulators – $8,500The project team membersDr Kathleen Doherty, Australian Red CrossBlood Transfusion Service, AdelaideDr G M Woods, Senior Lecturer, Disciplineof Pathology, University of Tasmania, HobartProfessor Emeritus H Konrad Muller, Disciplineof Pathology, University of Tasmania, HobartThe aim of the projectLangerhans cells are population anti-presentingcells. They have the unique capacity to presentantigen to naive T cells and induce immuneresponse. Because of this they are key regulators ofthe immune system. Evidence from our laboratorysuggested that immature Langerhans cells influencethe type of response that results. This projectevaluated Langerhans cells as modulators of theimmune response using them as a tool for turningoff damaging immune responses. From this work weaim to understand more about the development ofLangerhans cells and the way in which they caninduce an immune response.Achievements to dateThe development of Langerhans cells wasextensively analysed and we determined that theLangerhans cell network in neonatal mouse skingradually acquired the appropriate morphologyduring development. At day 4 the LC networkconsisted of just a number of rounded cells.By day 14 the network was fully dendritic andproduced an interlinking network. It wasdetermined that these cells undergo a distinctmaturation process during development. At day4 in neonatal skin in mice it was discovered thatthese Langerhans cells significantly alteredmorphology correlated to an altered functionsuch that they did not process and presentantigen as effectively as adult Langerhans cells.This meant that they would induce suppressionrather than immunity and consequently alteredthe immune response accordingly. The mostsignificant implication is that when a newbornanimal is exposed to antigen the immuneresponse is pushed towards suppressive ratherthan active immunity. Many of the moleculesexpressed on the surface of these cells wereanalysed to determine the difference of thesecells to normal cells.Additional funding obtainedA major grant was submitted to the NHMRC, andthis was successfully funded from the years 2000to 2002.Publications to the end of 20021. Dewar AL, Doherty KV, Woods GM, Lyons ABand Muller HK.(2001) Acquisition of immunefunction during the development of theLangerhans cell network in neonatal mice.Immunology; 103: 61-692. Woods GM, Doherty KV, Malley RC, Rist MJand Muller HK. Carcinogen modified dendriticcells induce immunosuppression byincomplete T cell activation resulting fromimpaired antigen uptake and reduced CD86expression. Immunology 2000; 99: 16-222. Muller HK, Doherty KV, Dewar AL, Chen YP,Toh BH and Woods GM. (2001) ImmatureLangerhans cells: Central role in toleranceinduction in carcinogen-treated and neonatalskin. Journal of Investigative Dermatology117: 1010; (abstr)A cross sectional study ofthe role of gender, pubitalstage, linear growth andphysical ability in kneecartilage development inchildren – $9,845The project team membersAssoc. Prof. Graeme Jones, Menzies Centrefor Population Health Research, HobartAssoc. Prof. Flavia Cicuttini, Monash UniversityThe aim of the projectIt is unclear why there are gender andcompartmental differences in the risk of kneeosteoarthritis. To test the hypothesis that thismay be associated with variations in cartilagedevelopment we investigated knee cartilagevolume in healthy children.Achievements to dateWe studied 92 children randomly selected fromyears 3-12 of a single Hobart school (males N=49,females N=43, response rate 76%, age range 9-18years). Articular cartilage thickness and volumewere determined at the patella, medial tibial andlateral tibial compartments by processing imagesacquired in the sagittal plane using T1-weightedfat saturation magnetic resonance on anindependent work station.Patron of the Research Foundation,Sir Max Bingham, cuts the caketo celebrate the Foundation’sthird birthday.8

Stem cell researcherDr Scott Ragg.Males had significantly more knee cartilage thanfemales. Gender explained between 6 and 36% ofthe variation in cartilage thickness and volume,which was statistically significant at all sites. Evenafter adjustment for age, body mass index, bonearea and physical activity, males had 16-31%higher cartilage volume, which was most markedat the medial tibial site. In addition, lateral tibialthickness was greater than medial tibial thickness(5.9 v 3.6 mm, p≤0.0001) and lateral tibial volumewas greater than medial volume (2823 v 2299 ?l,p≤0.0001). Furthermore, physical activity wasa significant explanatory factor for cartilagevolume at all sites (R 2 7-14% depending on site,all p≤0.05). The most consistent activityassociation was with vigorous activity in the lasttwo weeks (difference any versus none, 22-25%greater, all p≤0.05).We concluded that gender and joint compartmentdifferences in cartilage development may be oneexplanation for variations in the pattern of kneeosteoarthritis seen in later life. Furthermore, thephysical activity associations suggest thatcartilage development is amenable to modification.Additional funding obtained1999. Arthritis Foundation of Australia. AustralianRheumatology Association (Victoria) Grant-in-aid.G Jones, F Cicuttini. Longitudinal study of kneecartilage development in healthy children: the roleof gender, pubital stage, linear growth andphysical activity. Amount $8,0001999/2000. Masonic Centenary ResearchFoundation. G Jones, F Cicuttini. Is knee cartilagevolume reduced in the offspring of those whohave had knee replacement for non-traumaticosteoarthritis? Amount $26,4282000-2002. NHMRC Project Grant 106910. G Jones,F Cicuttini. A controlled longitudinal study ofknee cartilage volume in the offspring of subjectswith osteoarthritis of the knee. Amount $143,038Publications to the end of 20021. Jones G, Glisson M, Hynes K, CicuttiniF. Sex and site differences in cartilagedevelopment: a possible explanation forvariations in knee osteoarthritis in later life.Arthritis and Rheumatism 2000 43:2543-9.2. Jones G, Ding C-H, Hynes KL, Ma D, Glisson M,Cicuttini FM. Cartilage development inchildren: a longitudinal study of the effect ofgender, growth, Tanner stage and physicalactivity. Pediatric Research (submitted).3. C Ding, F Cicuttini, M Glisson, D Ma,K Hynes, G Jones. Linear Growth, Not PhysicalActivity, Is The Major Determinant Of KneeBone Size Development In Children.Osteoarthritis and Cartilage (submitted).Washing of haematopoieticstem cells prior toautologous transplantation:Is this a feasible clinicalpractice in cancertreatment? – $17,800The project team membersDr Scott Ragg, Senior Scientist, Stem CellTransplant Laboratory, Royal Hobart HospitalProf. Ray Lowenthal, Director of MedicalOncology, Royal Hobart HospitalThe aims of the projectBone marrow transplants are increasingly beingused to treat cancers such as leukaemia andlymphoma. Patients with a high risk of relapsemay have their own bone marrow harvestedduring remission, frozen in liquid nitrogen andsubsequently stored at ultra-low temperaturesuntil required for a transplant, sometimes yearslater. Dimethylsulfoxide (DMSO) is the principalcryoprotectant used in the cryopreservation ofhaematopoietic stem cells. During a transplant,DMSO is routinely reinfused intravenously alongwith the thawed cell products and is associatedwith a number of dose dependent DMSO infusionrelated toxicities including headache, nausea,abdominal cramping, flushing, decreased heartrate, neurological toxicity and increased bloodpressure.Many of these effects are due to DMSO-inducedhistamine release and the frequency of sideeffectscorrelates with the volume of infusedcryopreserved cells, the dose of DMSO and thevolume of cell lysis products infused. Acute renalfailure, heart attack or cardiac arrest have alsobeen reported as a result of contamination ofred blood cell lysates and DMSO. We wanted todevelop a protocol for washing the thawed cellsprior to transplant and hopefully reduce oreliminate these DMSO-related side effects. Sucha washing protocol must, however, have no effectupon the ability of the stem cells to safelytransplant the patient.Achievements to dateWe performed a validation study on a modifiedwashing protocol for use with cryopreserved bonemarrow and peripheral blood stem cell harvests.Parameters investigated included cell loss; overallviability, viable CD34 + stem cell enumeration,clonogenic potential and reduction in freehaemoglobin content. Overall cell viability wasimproved significantly by DMSO removal andenumeration of viable CD34 + HSC demonstratedthat washing did not reduce the number ofthese crucial cells. Similarly CFU-GM assaysdemonstrated that washing did not adverselyaffect the HSC clonogenic potential. Washingalso removed ≥90% of free haemoglobin (fromlysed red blood cells) from harvests. Our resultsdemonstrate that washing of cryopreserved stemcells does not have a significant negative impactand actually improves the outcome of several keyparameters. We concluded that a modified stemcell washing protocol is a feasible clinical practicewith the potential to reduce the morbidityassociated with the reinfusion of cryopreservedstem cells.Publications to the end of 20021. NE Wiggins, I Liew, KA Marsden, RM Lowenthaland SJ Ragg (2002) Multi-parametervalidation of a modified haematopoietic stemcell washing protocol. Cytotherapy (acceptedpending revision).2. Spurr, EE, Wiggins, NE, Marsden, KA,Lowenthal, RM and Ragg, SJ. (2002)Cryopreserved human haematopoietic stemcells retain engraftment potential afterextended (5-14 years) cryostorage.Cryobiology (in press).9

3. Validation of a Haematopoietic Stem CellWashing Protocol. Thesis submittedby Nicole Wright for Master of MedicalScience (Qualifying), Universityof Tasmania (2001).Antithrombotic prophylaxisin atrial fibrillation AND (in2000), Thromboprophylaxisin atrial fibrillation: closingthe gap between clinicaltrials and Australian practice– total $14,000The project team membersProf. Greg Peterson, University of Tasmania, HobartDr Janet Vial, Visiting Medical Officer, RoyalHobart HospitalMr Shane Jackson, PhD student,University of Tasmania, HobartThe 1998 and 2000 projects are related studies,directed at improving clinical outcomes inpatients with chronic atrial fibrillation, a majorrisk factor for stroke. This work forms part ofShane Jackson’s PhD program.The aim of the researchTo establish a register of patients with atrialfibrillation (AF) in the south of Tasmania fromcommunity practitioners and the Royal HobartHospital. The register will be used for thefollowing studies.• To assess antithrombotic usage in AF in thecommunity against current guidelines.• A risk benefit assessment of antithromboticuse in AF in the community setting.• For patients on warfarin, assess the benefit ofstrategies designed to improve anticoagulantcontrol on laboratory measures ofanticoagulation, thrombotic and bleedingcomplications.Achievements to dateWe have created an ongoing database of over 600patients with AF, and implemented educationalstrategies in a controlled trial to promote theappropriate use of antithrombotic drugs forinpatients with AF. A number of publications andconference presentations have resulted from thiswork and more are in development.Additional funding obtainedIn 2001, the project team was awarded aCommonwealth Department of Health and AgedCare, Quality Use of Medicines ResearchScholarship, valued at $75,000 (taken upby Shane Jackson).Publications to the end of 20021. Peterson GM. (1999). Antithrombotictreatment for atrial fibrillation: patientsmust be told full details of risks of treatment(letter). BMJ 319: 708.2. Jackson SL, Peterson GM, Vial JH, Daud R, AngSY. (2001). Outcomes in the management ofatrial fibrillation: clinical trial results canapply in practice. Internal Med J 31: 329-36.3. Peterson G, Jackson S. (2001). Long termanticoagulation or antiplatelet treatment.Garbage in equals garbage out. (letter).BMJ 2001; 323: 233.4. Peterson GM, Boom K, Jackson SL, Vial JH.(2002). Doctors’ beliefs on the use ofantithrombotic therapy in atrial fibrillation:identifying barriers to stroke prevention.Internal Med J 32: 15-23.5. Peterson G, Jackson S, Bereznicki L. (2002).Stroke prevention: anticoagulation for atrialfibrillation in the elderly. Aust Pharmacist21: 203-6.6. Peterson G, Jackson S. (2002). Reducing thehazards of anticoagulation in elderly patientsthrough near-patient testing by pharmacists.Aust Pharmacist 21: 679-81.1999A study of iodine nutritionand thyroid disease inpregnancy and thepostpartum period – $10,350Dr John Burgess, Director, EndocrinologyLaboratory, Royal Hobart HospitalDr A Kemp, Dr T Greenaway, Dr A Platts,Dr L Brothers, Dr V Parameswaran, R FearnleyThe aim of the researchThis study assessed almost 500 women during thefirst, second and third trimesters of pregnancy inrelation to iodine nutrition (urine iodine excretion),thyroid function (TSH, FT4 and ATPO) and thyroidsize and texture (thyroid ultrasonography).Achievements to dateA proportion of women and their babies hasalso been assessed post-partum. The researchhas identified mild iodine deficiency in womenparticipating in the study. A summary of theresults has been provided to the Departmentof Public Health.Publications to the end of 2002Preliminary data have been presented in abstractform at the International Congress of Endocrinology.A number of specific manuscripts related to thisresearch will be prepared for publication.The incidence ofasymptomatic Guillain-BarreSyndrome (GBS) followingcampylobacter infections– $3,400The project team membersDr Bruce Taylor, Head of Neurology,Royal Hobart HospitalDr Jan Williamson, Medical Scientist,Royal Hobart HospitalMr David Coleman, Scientific Officer, Departmentof Health & Human ServicesDr Bruce Taylor, Chair of the RHHResearch Advisory Committee.10

Dr Alastair McGregor, Pathologist,Royal Hobart HospitalThe aim of the researchThis project aims to perform nerve conductionstudies on patients with documentedcampylobacter infections within three weeks ofthe infection commencing or at around the timethat GBS would develop following an acutecampylobacter infection.Achievements to dateTo date we have enrolled a total of 40 patientswho have all had nerve conduction studies andhave completed a neurological exam andquestionnaire. We are planning to enrol a totalof 50 patients and this hopefully will be completeby May 2003. We have not detected anyasymptomatic GBS cases to date.The Glaucoma InheritanceStudy Tasmania – GIST, andInvestigation of mutations inOPA1 gene in glaucomafamilies seen by the GISTstudy – total $23,177The project team received an initial $11,177 for theglaucoma study in 1999, and a further $12,000 in2002 for the OPA1 gene investigation. The reportbelow concentrates on GIST, with an update onthe resulting gene research to be provided innext year’s report.The project team membersAssociate Prof. David Mackey, Ophthalmologist,Royal Hobart HospitalDr Joanne Dickinson, Post Doctoral Fellow, MenziesCentre for Population Health ResearchDr Jamie Craig, Flinders Medical Centre, AdelaideRobin Wilkinson, Orthoptist in Charge,Eye Clinic, Royal Hobart HospitalThe aim of the researchThe Glaucoma Inheritance Study is a collaborativeproject of Tasmanian ophthalmologists, the RoyalVictorian Eye and Ear Hospital, the Royal HobartHospital, the Menzies Centre and the Centre forEye Research Australia (CERA) in Melbourne.Glaucoma is a group of eye disorders involvingdamage to the optic nerve and loss of peripheralvision, which may result in blindness if leftuntreated. Glaucoma is believed to affect 210,000people in Australia with 10% of these unable tohold a driver’s licence. Of the 67 million peopleaffected worldwide, 7 million are bilaterally blindas a result of the disease. Approximately half ofthe affected individuals may remain undiagnoseddue to the painless and chronic progression ofmost forms of glaucoma.The Glaucoma Inheritance Study in Tasmania(GIST) is the largest population-based study ofglaucoma genetics in the world. The aim of thisproject is to identify the genes that increase anindividual’s susceptibility to the disease. Thestudy involves over 2,000 individuals diagnosedwith glaucoma and approximately 400 familiesfrom Tasmania and mainland Australia. Blood hasbeen collected from approximately 1,700 peoplein 120 Tasmanian families. The study provides thepower to undertake a wide range of genetic andepidemiological research.To date, little is known about the geneticsof glaucoma. One gene, myocilin, has beenassociated with 3-5% of primary open angleglaucoma (POAG). Families from the GIST, togetherwith families collected by our collaborators at theUniversity of Iowa, were used to first identify thisgene’s role in glaucoma. For one aspect of thisresearch, we have selected the largest primary openangle glaucoma (POAG) families for investigationof five chromosomal regions tentatively reported tocontain genes involved in glaucoma. Positive resultswill allow for refinement of the region of interestand candidate gene approaches will be used toidentify the gene at each genomic location.Collaborators for the project are the Centre for EyeResearch Australia at the University of Melbourne,the University of Iowa and the University of Oregon.Achievements to dateParticipation in the identification of the GLC1Agene and analysis of its importance and clinicalpresentation with glaucomaPublications to the end of 20021. Baird PN, Craig JE, Richardson AJ, Ring MA,Sim P, Stanwix S, Foote SJ, Mackey DA.Analysis of 15 primary open-angle glaucomafamilies from Australia identifies a foundereffect for the Q368STOP mutation of Myocilin.Hum Genet. 2003;112:110-6.2. Mackey DA, Craig JE. Glaucoma InheritanceStudy in Tasmania: An InternationalCollaboration. American Academy ofOphthalmology San Francisco 2002 BasicClinic Sciences Course Section 13 InternationalOphthalmology, Part 5. CollaborativeResearch. XXXIII Pg 265-269.3. Vickers JC, Craig JE, Stankovich J, McCormackGH, West AK, Dickinson JL, McCartney PJ,Coote MA, Healey DL, Mackey DA. Theapolipoprotein [epsilon]4 gene is associatedwith elevated risk of normal tensionglaucoma. Mol Vis. 2002;8:389-393.4. Sale MM, Craig JE, Charlesworth JC, FitzGeraldLM, Hanson IM, Dickinson JL, Matthews SJ,Heyningen Vv, Fingert JH, Mackey DA. Broadphenotypic variability in a single pedigreewith a novel 1410delC mutation in the PST domainof the PAX6 gene. Hum Mutat 2002;20:322.5. McLean IM, Mueller E, Buttery RG, Mackey DA.Visual field assessment and the Austroaddriving standard. Clin and Exp Ophthalmol.2002 30:3-7.6. Craig JE, Baird PN, Healey DL, McNaught AI,McCartney PJ, Rait JL, Dickinson JL, Roe L,Fingert JH, Stone EM, Mackey DA. Evidence forgenetic heterogeneity within eight glaucomafamilies, with the GLC1A Gln368STOP mutationbeing an important phenotypic modifier.Ophthalmology 2001; 108:1606-1620.7. Mitchell P, Cumming RG, Mackey DA. Author’sreply. Ophthalmology 2001;108:8378. Baird PN, Dickinson J, Craig JE, Mackey DA.The Taa1 restriction enzyme provides a simplemeans to identify the Q368STOP mutation ofthe myocilin gene in primary open angleglaucoma. Am J Ophthalmol 2001; 131:510-511.9. Dickinson JL, Sale MM, Craig JE, Mackey DA.Laboratory methods in ophthalmic genetics:obtaining DNA from patients. OphthalmicGenet 2001; 22:49-60.10. Nishimura DY, Searby CC, Alward WLM, WaltonD, Craig JE, Mackey DA, Kawase K, Kanis AB,Patil SR, Stone EM, Sheffield VC. A spectrumof FOXC1 mutations suggests gene dosage as11

a mechanism for developmental defects of theanterior chamber of the eye. Am J Hum Genet2001; 68:364-372.11. Fingert JH, Clark AF, Craig JE, Alward WLM,Snibson GR, McLaughlin M, Tuttle L, MackeyDA, Sheffield V, Stone EM. Evaluation of themyocilin (MYOC) glaucoma gene in monkeyand human steroid-induced ocular hypertension.Invest Ophth Vis Sci 2001; 42:145-52.12. McNaught AI, Allen JG, Healey DL, McCartneyPJ, Coote MA, Wong TL, Craig JE, Green CM,Rait JL, Mackey DA. Accuracy and implicationsof a reported family history of glaucoma:experience from the Glaucoma InheritanceStudy in Tasmania. Arch Ophthalmol 2000;118:900-904.13. Mitchell P, Cumming RG, Mackey DA. InhaledCorticosteroids, family history and risk ofglaucoma. Ophthalmology 1999; 106:2301-6.14. Simm RM, Fingert JH, Craig JE, McNaught AI,Mackey DA. Normal range of hearingassociated with Myocilin Thr377Met.Ophthalmic Genetics 1999; 20:205-7.15. Fingert JH, Héon E, Liebmann JM, Yamamoto T,Craig JE, Rait J, Kawase K, Hoh S-T, Buys YM,Dickinson J, Williams-Lyn D, Trope G,Kitazawa Y, Ritch R, Mackey DA, Alward WLM,Sheffield VC, Stone EM. Analysis of myocilinmutations in 1703 glaucoma patients from fivedifferent populations. Hum Mol Genet 1999;8:899-90516. Craig JE, Mackey DA. Glaucoma Genetics:where are we? Where will we go? Curr OpinOphthalmol 1999;10:126-34.Immature Langerhans cellsand lymphoid dendritic cellsas a potential therapy forautoimmune disease– $10,000The project team membersDr G M Woods, Senior Lecturer, Disciplineof Pathology, University of Tasmania, HobartEmeritus Professor \H Konrad Muller, Disciplineof Pathology, University of Tasmania, HobartThe aim of the researchAutoimmune diseases occur when the immunesystem attacks the body. Current treatment relieson drugs to provide temporary relief rather thana cure. This project evaluated novel immunisationstrategies using a population of cells known asdendritic cells to prevent the development ofautoimmune disease. The disease evaluated wasautoimmune haemolytic anaemia which is similarto the human disorder pernicious anaemia.Achievements to dateIn early experiments we were able todownregulate the development of disease inautoimmune prone mice. This was refined usingthe high responder strain, BALB/c CrSlc mice,which were used in experiments involvinggastritis therapy via neonatal treatment withautoantigens. Efforts here have involved the useof a 14-mer peptide from the b-subunit of gastricH+/K+-ATPase enzyme in combination withadjuvants such as DNFB and TNCB. All attemptsto downregulate gastritis using this peptide havebeen unsuccessful, which raises the possibilitythat this peptide is unsuitable for processing andpresentation by antigen presenting cells, andtherefore unsuitable to be used in attemptsto downregulate autoimmune gastritis.An animal model was established whereby theautoimmune disease could be studied. When micewere pre-treated with tolerogenic dendritic cells,the onset of the disease was significantly delayed.This indicated that such a treatment using apopulation of tolerogenic dendritic cells couldoffer hope for new treatments of autoimmunediseases such as diabetes and lupus. This workwas performed in mice and the tolerogenicdendritic cells were produced by applying theautoantigen through neonatal skin. The neonatalskin contained a population of immature dendriticcells which, when activated, induced suppressedtolerance rather than immunity, which effectivelycurtailed the development of autoimmune disease.Additional funding obtainedOn the basis of this work a major grant wassubmitted to the National Health and MedicalResearch Council and this was successfully fundedfor years 2000 to 2002.Publications to the end of 20021. Chen YP, Muller HK, Scarff K, Toh BH andWoods GM. Induction of peripheral tolerancein neonatally thymectomised mice byimmunisation through chemical carcinogenalteredskin. Cellular Immunology1998;189:99-1062. Woods GM, Chen YP, Dewar AL, Doherty KV,Toh BH and Muller HK (2001) Prevention ofautoimmunity by induction of cutaneoustolerance. Cellular Immunology 207:1-53. Muller HK, Doherty KV, Dewar AL, Chen YP, TohBH and Woods GM. (2001) ImmatureLangerhans cells: Central role in toleranceinduction in carcinogen-treated and neonatalskin. Journal of Investigative Dermatology117:1010; (abstr)4. Woods GM, Chen YP, Doherty KV, Dewar AL,Toh BH and Muller HK. Modification ofdendritic cell function – Implications forautoimmunity and cancer. First annualscientific meeting of the Haematology Societyof Australia and New Zealand, Hobart,Tasmania, October 1999.5. Woods GM, Chen YP, Doherty KV, Toh BH andMuller HK. Protection against autoimmunedisease by immunisation through skincontaining immature Langerhans cells. SixthInternational Symposium on Dendritic Cellsin Fundamental and Clinical Immunology,Port Douglas, Australia, May 2000.2000Identification of genescausing congenital cataract– $3,916The project team membersMs Kathryn Burdon (nee Flowers),Menzies Centre for Population Health ResearchProf. Konrad Muller (foreground)and Dr Greg Woods.12

Heather Ellen, Foundation ExecutiveDirector during 2000, skillfullyplaced the organisation ona firm footing.Dr Michele Sale, Menzies Centre for PopulationHealth ResearchAssociate Prof. David Mackey, Ophthalmologist,Royal Hobart HospitalThe aim of the researchSeveral crystallin genes are known to causecongenital cataract. This project aimed to screenthese five genes for mutations causing congenitalcataract in 39 families from Tasmania andVictoria, to exclude these families from furtherstudies to identify novel cataract genes.Achievements to dateThe initial protocol was to use fluorescentlylabelled primers and detect mutations usingcapillary electrophoresis on an ABI 310. However,it became apparent that this method was notsensitive enough due to problems with controllingthe temperature and leaving samples on themachine for extended periods. Subsequently,it was decided to do the screening usingtraditional radiolabelling and gel basedtechniques. This method detected one causativemutation and four polymorphisms.The causative mutation was a disruption to asplice site in the Crystallin-β A1 gene in a largeVictorian family.The mutation was previouslyreported in an Indian family with a similarcataract phenotype. Three polymorphisms weredetected in this gene. One silent polymorphismin codon 152 that had no effect on the amino acidsequence as well as two intronic polymorphisms.Neither segregates with disease. A splice sitemutation was also detected in the Crystallin-βA1gene but, again, it does not segregate withdisease in the small family in which it was found.Additional funding obtainedRoyal Hobart Hospital Research Foundation MajorGrant 2002 – The Identification of Genes CausingCongenital Cataract – $15,000Publications to the end of 2002The data will be submitted for publication alongwith results obtained from the above RHHResearch Foundation Major Grant.Regaining control ofleukaemia cell growth:the role of c-fos and c-junin ceramide signalling– $4,000The project team membersCharles Connor, PhD student, Oncology Lab,University of Tasmania (Current position: forensicscientist, Department of Police & Public Safety,Hobart)Dr Greg Woods, Senior Lecturer, Departmentof Pathology, University of TasmaniaDr Scott Ragg, Senior Scientist, Stem CellTransplant Laboratory, RHHThe aim of the researchConventional approaches to leukaemia therapy arebased on killing the aggressively growing cancercells using chemotherapy and/or radiation. Analternative approach is to trigger the leukaemiacells to mature into cells that are unable to divideand eventually die. We have shown that thenaturally occurring lipid, ceramide, consistentlycauses growth arrest and activation of tumoursuppressor proteins in leukaemia cells. Inaddition, expression of the c-fos and c-junregulatory genes is increased in these treatedcells. An understanding of the roles of ceramideinducedc-fos/c-jun expression will hopefullyprovide better understanding of the potentialfor ceramide in the treatment of leukaemia.Achievements to dateWe had initially hoped to insert active formsof the fos and jun genes into leukaemia cellsusing a technique called electroporation.However, our studies quickly showed that theapproach was not going to give us results thatcould be analysed. We tried several differentmethods of gene insertion but none of these gaveus sufficiently high enough levels of geneexpression. This work lead us to realise that thequestion we were seeking to answer would haveto be approached in a different manner.Additional funding obtainedRHH Research Foundation 2001 Starter Grant: Role ofthe AP-1 Transcription Complex in Lipid-InducedDifferentiation of Leukaemia Cells – $5,500\Publications to the end of 20021. The role of c-Jun and c-Fos in ceramideinducedmyeloid differentiation. Thesissubmitted by Olivia McQuestin for Bachelor ofScience with Honours, University of Tasmania,2001. (Awarded First Class Honours)2. The mechanisms of ceramide-inducedterminal differentiation of myeloid leukaemia.Doctoral thesis being prepared by CharlesConnor, University of TasmaniaInvestigation of delayedplatelet recovery in bonemarrow transplant patients– $4,000The project team membersNicole Wright, Senior Scientist, Stem CellTransplant Laboratory, Royal Hobart HospitalDr Scott Ragg, Senior Scientist, Stem CellTransplant Laboratory, Royal Hobart HospitalThe aim of the researchBone marrow transplants are increasingly beingused to treat cancers such as leukaemia andlymphoma. Patients with a high risk of relapsemay have their own bone marrow harvestedduring remission, frozen in liquid nitrogen andsubsequently stored at ultra-low temperaturesuntil required for a transplant, sometimes yearslater. A previous study showed that patientswhose bone marrow cells were stored for periodslonger than 12 months had a delayed recovery intheir platelet cells post-transplant compared topatients whose cells were stored short term (lessthan 12 months). As platelet cells are essentialfor controlling bleeding and clotting, this delaycould have serious consequences for patients.13

This study aimed to determine whether thedelayed platelet recovery is due to an insufficientnumber of platelet precursors in the long termstored bone marrow harvests.Achievements to dateForty archival samples of transplant material weregrown in semi-solid media containing growthfactors specific for platelet precursors. 20 sampleshad been stored for 12 months or less (short termstorage group), 20 samples had been stored fortwo years or more (long term storage group).Analysis shows that there was no significantdifference in the number of platelet precursorsbetween these two groups. Hence the delayedplatelet engraftment was not due to reducednumbers of platelet precursors in the material thathad been stored long term, and therefore otherfactors had to be the cause of this problem(such as type and intensity of prior chemotherapyand whether the patient had received radiationtherapy). This work was partly performedby a medical student undertaking a 4th yearAdvanced Study course, thus allowing herto gain experience in medical research.\2001Major GrantsThe link betweenparasuicide, completedsuicide and serviceutilisation in Tasmania– $14,300The project team membersDr Brett Daniels, Intern, Royal Hobart HospitalDr Simon Brown, Emergency Physician,Royal Hobart HospitalProfessor Ken Kirkby, Professor of Psychiatry,University of TasmaniaThe aim of the researchThe team’s aim was to determine the frequency ofprogression from deliberate self harm to completedsuicide in the population of patients presentingto the Department of Emergency Medicine at theRoyal Hobart Hospital with an episode of deliberateself harm during the period 25 September 1990 to20 January 2001.They then sought to identify riskfactors associated with a greater tendency to dieby suicide following an episode of deliberate selfharm. It was then planned to make recommendationswhich may reduce the frequency of progression tocompleted suicide following an episode ofdeliberate self harm.Achievements to dateThe project examined data from 3,940 cases ofdeliberate self harm presenting to the Departmentof Emergency Medicine at the RHH from 1990 to2001. These data were linked with suicide data fromthe Coroner’s Office. It was found that fewer than1% of the study cases of deliberate self harm hadlater gone on to die by suicide. This was arelatively low rate of progression from deliberateself harm to completed suicide, when comparedwith similar studies from other locations. The studyalso identified a number of factors that may beused to identify patients at particularly high riskof this progression. Further research will beconducted in this area in a bid to reducethis phenomenon.Hip cartilage volume inhealthy adults: normativedata, gender differencesand relationship to kneecartilage, cartilagebiochemistry and lifestylefactors – $13,200The project team membersAssoc. Prof. Graeme Jones, Menzies Centrefor Population Health ResearchAssoc. Prof Flavia Cicuttini, Monash UniversityThe aim of the researchHip osteoarthritis is a common cause of disabilitywith up to 10% of the elderly population sufferingthis condition. While hip replacement is veryeffective at treating this condition it is costly andpatients face a wait of two years to have this done.Osteoarthritis takes many years to develop andpreventive strategies have not been developed dueto the lack of a measure of presymptomatic disease.Achievements to dateRecently, we have developed a novel accuratemethod of in vivo assessment utilising MRI forboth the knee and hip. We have recentlypublished our knee development study in Arthritisand Rheumatism (the number one ranked arthritisjournal) indicating the interest this has generatedas well as the novelty of the work. This has alsoled to further NHMRC funding in the area ofgenetics of knee cartilage volume and preventionof knee osteoarthritis. Virtually no data areavailable for hip cartilage.We propose a cost-effective study of hip cartilagedevelopment by studying the controls in thisNHMRC funded study of knee cartilage. Thehypotheses to be tested are the following:• Unlike knee cartilage, hip cartilage volumeis not different between asymptomatic malesand females aged 20-60 years living inmetropolitan Hobart and randomly selectedfrom the electoral roll• Hip cartilage volume is negatively associatedwith measures of cartilage turnover• Hip cartilage volume is negatively associatedwith body mass index and positivelyassociated with measures of physical activity(strength, aerobic fitness, and questionnaire)• Hip cartilage volume correlates weakly butsignificantly with knee cartilage volumeProgress has been slow on this study due to theneed to upgrade the MRI machine software atRHH. This has happened and approximately 100subjects have been measured to date. Analysisof this data will occur later this year.Nicole Wright (formerly Wiggins)in the RHH Stem Cell Laboratory.14

Assoc. Prof. Sylvia Kirov.Roles of the lateralflagellum in bacterial-hostinteractions – $16,500ResearcherAssoc. Prof. Sylvia M. Kirov, MedicalMicrobiology, University of TasmaniaThe aim of the researchMost bacterial infections (particularly persistentones), and the transfer of antibiotic resistance arelinked to the formation of communities ofbacteria (biofilms) on host tissues or medicaldevices. Environmental biofilms are alsoimportant sources of infection. Our research aimsto understand the fundamental processesinvolved in biofilm formation so as to identifycritical points that may be targeted with newanti-infective strategies to combat thesesignificant problems. Bacterial motility structures(flagella) are known to contribute to biofilmformation but very little is known about theirmultifunctional roles and how they are controlled.The bacteria we are studying, Aeromonas species(cause of gastrointestinal infections), are an idealmodel for examining these questions as theypossess two distinct flagellar motility systems(polar and lateral), which mediate ‘swimming’motility in liquid environments and ‘swarming’motility on surfaces, respectively, unlike mostbacterial species that have only one flagellar typefor both functions. This has enabled us to producemutant strains that lack particular flagellarfunctions so that the contribution of each canbe independently evaluated in in vitro biofilmmodels. The major aim of this project was to testthe hypothesis that swarming motility (mediatedby lateral flagella in Aeromonas species) is criticalfor biofilm formation on abiotic (glass, plastic)and human cell surfaces (epithelial and intestinal).Achievements to dateRHHRF funding facilitated the completion ofswarming motility studies with specific mutantstrains that proved definitively that the lateralflagellum is responsible for surface movement inAeromonas species. The work was published in thehighly ranked American Journal of Bacteriologyand presented at the annual ASM meeting in Perth,WA. Biofilm assays were established, optimised,and used to investigate a panel of 14 mutants withdefects in polar and lateral flagellar expressionand functions. It was shown that both polar andlateral flagella make significant contributions(through both adhesion and motilities) to biofilmformation on glass and a range of human cells.These results strengthened our NHMRC applicationfor Project Grant funding, cemented ourcollaboration with Dr Jon Shaw at the University ofSheffield, UK, and led to a new collaboration withDr Simon Swift, University of Auckland, NZ. Theabove biofilm studies were presented at the annualAustralian Society for Microbiology conference inMelbourne in October 2002, and subsequentlywritten up for publication.Additional funding obtainedUniversity of Tasmania Institutional ResearchGrants Scheme 2002 – “The roles of bacterialsurface structures in mucosal colonisation”– $20,500University of Tasmania Visiting Scholars’ Scheme 2001(Dr J. G. Shaw, University of Sheffield, UK) – $4,000Publications and activities to theend of 2002Journal article:Kirov, S. M., B. C. Tassell, A. B. T. Semmler, L. A.O’Donovan, A. A. Rabaan, and J. G. Shaw. 2002.Lateral flagella and swarming motility inAeromonas species. J. Bacteriol. 184:547-555.Book chapters:1. Kirov, S. M. Aeromonas and Plesiomonas. pp.301-327 In Food Microbiology: Fundamentalsand Frontiers, 2nd edition, Doyle, M.P.,Beuchat, L. R. and Montville, T. J. (eds.).American Society for Microbiology,Washington D. C. 2001.2. Kirov, S. M. Aeromonas spp. In FoodborneMicroorganisms of Public Health Significance.6th edition, AIFST (NSW Branch) FoodMicrobiology Group, Australia. (≥25 publishedpages); submitted June 2002.Conference abstracts:1. Tassell, B. C., and S. M. Kirov. The lateralflagellum mediates swarming motility inAeromonas species. Microbiology Aust. 2001.22: Abstr.P.2.1, p. A1202. Tassell, B. C., and S. M. Kirov. The lateralflagellum mediates swarming motility inAeromonas species. Medical Research WeekPoster Abstracts, 2001. Abstr. L10, p.11.3. Kirov, S. M., B. C. Tassell, M. Castrisios, andJ. G. Shaw. Flagellar activities and biofilmformation. Microbiology Aust. 2002.Submitted May, 2002.4. Kirov, S. M., B. C. Tassell, M. Castrisios,A. A. Rabaan, and J. G. Shaw. Functionsof bacterial flagella. Microbiology Aust.2002. Accepted July 2002.Invited review and lectures:MiniReview article, FEMS Microbiology Letterson the ‘current status of lateral flagella’ (Dr G.M. Ihler, Reviews Editor, Texas, USA).Invited lecture, 7th International Symposiumon Aeromonas and Plesiomonas, Orihuela, Spain,September, 2002. (Dr A. J. Martinez-Murcia,Chairperson Organizing Committee). Workpresented by Dr J. Shaw.Invited lecture, Symposium on ‘Bacterialadhesion’, Annual Conference of the AustralianSociety for Microbiology, Melbourne, October,2002. (Dr E. Hartland, Scientific OrganizingCommittee).The use of proteomics forprotein characterisation ofthe diseased state – $16,500The project team membersDr Roger Lord, Lecturer (Surgery),University of TasmaniaDr Kiron Bhatia, Surgical Trainee,University of TasmaniaProfessor Peter Stanton, University of Tasmania15

The aim of the researchThe global analysis of cellular proteins hasrecently been termed proteomics, which is anadvanced area of research developing in the postgenomeera. Proteomics uses a combination ofsophisticated techniques involving twodimensionalgel electrophoresis, image analysis,mass spectrometry, amino acid sequencing andbio-informatics to quantify and resolve proteins.The application of proteomics provides majoropportunities to elucidate disease mechanismsand to identify new prognostic markers andtherapeutic targets. This methodology will providenew insights into human disease conditionsranging from cancer to infectious diseases.Achievements to dateSome of the immediate areas we wish to exploreinclude: (1) new markers and targets of breastcancer, in particular, secondary tumours forwhich no markers of effective intervention exist(2) a closer examination of the mechanismsinvolved in transplantation tolerance andrejection with regard to hepatic transplants(3) protein characterisation of different typesof cardiomyopathy to understand the ‘triggers’involved in these ill-defined states of heartfailure. This is however only a small list ofprojects to which this state-of-the-art separationtechnology might be put to good use ifincorporated into other projects within boththe hospital and university.Publications to the end of 20021. Lord R, Vari F, Goto S. LSF-1 Expression onrecipient lymphoid cells correlates withallograft survival following orthotopic livertransplantation. Australian Surgical MedicineResearch Conference, Hobart, 2001.2. Lord R, Vari F, Goto S. The expression ofan immunosuppressive protein (LSF-1) onlymphoid cells correlates with allograft survivalfollowing orthotopic liver transplantation.Surgical Research Society of Australasia AnnualScientific Meeting, Hobart, 2001.Clinical significance ofexpression of the bonemarrow homing receptor,CXCR4, on human CD34 +stem cells – $11,000The project team membersDr Scott Ragg, Senior Scientist, Stem CellTransplant Laboratory, RHHDr Katherine Marsden, Director,Department of Pathology, RHHThe aim of the researchStem cell transplantation can cure patientswith cancer and a key to successful transplant isensuring that an adequate number of CD34 + bloodstem cells is given to the patient. The transplantedstem cells are put into the patient’s bloodstreamand ‘home’ back to the bone marrow where theystart repopulating the cells that were destroyedby chemotherapy. Recently, the ‘homing receptor’that enables the CD34 + stem cells to find their wayback to the bone marrow was determined. Thisreceptor, called CXCR4, is not expressed by allCD34 + stem cells. Our goal was to enumerate thenumber of CXCR4 + /CD34 + stem cells that we arecollecting and transplanting into cancer patientsand determine whether this number correlateswith transplant success.Achievements to dateWe analysed the CXCR4 expression on the stemcells of 45 patients who had a blood or marrowstem cell harvest at the RHH. We found that CXCR4was expressed on at least 90% of the CD34 + stemcells of each patient. However, the amount ofCXCR4 on the stem cells showed a greater interpatientvariation with some patients having alow density and some patients having a relativelyhigh density. Further analysis of this projectwill occur as patients are transplanted with theirfrozen blood stem cells. We will monitor thenumber of days it takes for their blood cell countsto recover after the transplant and correlate thisboth to the number of CXCR4 + /CD34 + stem cellsthat were transplanted and also the densityof the CXCR4 expression.Multi-centre ‘B-Aware’ trialwith the Aspect A2000 BISmonitor – $16,500The project team membersDr Stephen Swallow, Staff Specialist Anaesthetist,Royal Hobart HospitalTamara Clennent, Research Nurse, OperatingTheatres, Royal Hobart HospitalThe aim of the researchThe Royal Hobart Hospital is one of 25 centres inAustralia, New Zealand and Hong Kong that aretaking part in a randomised, blinded study todetermine if use of the BIS monitor, Aspect MedicalSystems, can reduce the incidence of awarenessin high risk patients who receive a generalanaesthetic that includes a muscle relaxant.The Chief Investigators for the overall trial areAssoc. Prof. Paul Myles from the Alfred Hospital,Melbourne and Assoc. Prof. Kate Leslie from theRoyal Melbourne Hospital.The trial overall has been supported, amongothers, by the College of Anaesthetists and byAspect Medical Systems.Achievements to dateTo date, 1,900 patients have been enrolled intothe study. In Hobart we have recruited 40patients. Sample size calculations indicated thatthe study will require a total of 2,500 patients. Itis hoped that patient recruitment will be completetowards the end of this year.Data analysis will occur early in 2003 and it is tobe hoped that results from this study might bepublished at the College of Anaesthetists GeneralScientific Meeting in Hobart in May 2003. If thisstudy returns a result that use of the BIS monitorwith titration of anaesthetic depth to a BIS valuebetween 40 and 60 reduces the frequency ofawareness under anaesthesia for high riskpatients, this will be the first time that a monitorhas been able to usefully determine the depthof anaesthesia in a clinical setting.The Tasmanian Chorale providesa singing sponsorship at the2002 Big December Breakfast.16

The group in Hobart applied only to the RHHResearch Foundation. Our successful applicationmeans that we have been able to pay a part timeresearch nurse, Tamara Clennent, lease a computerfor use in the trial, and we may be able to purchaseone or both of the BIS monitors which we currentlyhave on loan from Aspect. Anaesthetists at theRoyal Hobart Hospital have been able to use the BISmonitors and gain clinical experience with them.Assessment of the crossreactivity between anticampylobacterantibodiesand anti-gangliosideantibodies in humanneuropathic disorders – $11,000The project team membersDr Bruce Taylor, Head of the Departmentof Neurology, Royal Hobart HospitalDr Jan Williamson, Mr David Jones,Mr David Coleman, Dr Alastair McGregorThe aim of the researchThis project aims to study the interactions/sharedreactivities of campylobacter antibodies andganglioside antibodies. Based on the hypothesisthat Guillain-Barre Syndrome arises following anacute campylobacter infection in up to 30% ofcases and that anti-campylobacter antibodies aremore commonly seen in GBS than in controls withor without a preceding infection.Achievements to dateWe have studied campylobacter antibody profilesin 98 patients with acute campylobacter infectionsand have also studied a variety of antigangliosideantibodies in the same patient group.We have performed correlation matrices, andhave found no relationships. We have also usedtwo methods to more specifically look at crossreactivity. In the first method antibodies wereseparated using a cephadex column and thensolubilised and passed through a second columncontaining the other antigen. This showed noclear dual binding. Secondly we performedwestern blot analysis of anti-campylobacterantibodies and anti-ganglioside antibodieslooking for shared specificity. Again we wereunable to determine any cross reactivity.Publications to the end of 2002This project is now complete and will bepresented at the Australian Association ofNeurologists’ meeting in May 2003, and amanuscript is under preparation.The Foundation’s Administrative Officer,Natasha Beveridge.Taxol: a new treatmentfor preventing neuronaldegeneration followingbrain trauma – $13,200The project team membersJyoti Chuckowree, PhD student, UTAS Disciplineof PathologyProfessor James Vickers, Head, UTAS Disciplineof PathologyThe aim of the researchThis project focussed on whether a therapeuticagent, taxol, currently utilised for treating cancerin humans, may potentially have beneficialeffects for the consequences of brain trauma.The central nervous system is a complex assemblyof neurons (nerve cells) and their supportingmatrix. Neurons are polarised cells, consistingof a cell body and an array of fine projections,or neurites. Neurites are essential for informationtransfer within the nervous system and fall intotwo categories: dendrites, which are responsiblefor capturing information and passing it to theneuronal cell body, and axons, which transferinformation from the cell body to other neuronsor targets. The elongated, slender and fragilenature of axons makes them particularlyvulnerable to physical injury, such as thatoccurring following human head trauma. Untilrecently, damaged axons in the central nervoussystem were believed to be incapable of repair,but accumulating evidence now suggests thatdamaged axons have the ability to sprout andpossibly regenerate following injury, and thatreorganisation of the cytoskeleton, the network ofsupportive filamentous proteins within cells,plays a central role in this process. Abnormalaxonal sprouting, however, has been implicatedin the development of epileptic brain activityfollowing brain trauma and the evolvingpathology of Alzheimer’s disease. In a novelapplication, we have utilised a novel model ofaxonal injury to cultured neurons, developed atthe University of Tasmania Clinical School,capable of eliciting a substantial axonalsprouting response, to investigate whether taxolhas the capacity to inhibit post-injury sprouting.Taxol binds to and stabilises the proteins thatform the cytoskeleton of axons.Achievements to dateIn cultured cortical nerve cells, taxol exposureduring development resulted in the distensionsof nerve cell processes and the formation ofbulbous structures at neurite tips, which replacedthe typical fan-shaped growth cones responsiblefor axon guidance. Quantitative analysisdemonstrated that taxol significantly impairedgrowth cone formation and neurite elongation.Exposure to taxol in the post-injury period hada profound effect on the sprouting response oftransected axons; significantly reducing bothsprout outgrowth and elongation after injury.Moreover, sprouts elaborated from taxol-treatedprocesses were tipped by bulb-like structuressimilar to those existing at the tips of taxoltreated developing neurites. Alterations causedby taxol exposure were partially reversible inboth developing and mature, injured cultures.These results indicate that similar microtubuledynamics underlie neurite development and thesprouting response generated in injured axons.Moreover, microtubule disruption, using agentssuch as taxol, could be useful in preventing themaladaptive sprouting response that mayunderlie post-trauma epilepsy andAlzheimer’s disease.17

Starter Grants– round 1Is leather better after all?A comparison of two stylesof wrist splints and theireffectiveness in reducingpain and improving functionin patients with wrist painresulting from rheumatoidarthritis, osteoarthritis ora wrist injury – $3,224The project team membersJill Thiele, Senior Occupational Therapist,Royal Hobart HospitalWendy Rowell, Manager Occupational Therapy,Royal Hobart HospitalThe aim of the researchThis study will formally assess the effectivenessof leather splints as compared to the commonlyprescribed commercial elastic splints in patientswith wrist pain resulting from rheumatoid arthritis,osteoarthritis and wrist trauma. Patients presentingwith wrist pain or disease that significantlyinterferes with function will trial wear eachof the two types of orthoses. Comparisons will bemade to determine whether leather is significantlybetter than the other styles. As leather splints taketwo hours to make as compared with five minutesto fit the commercial splint, the improvement willneed to be significant to recommend a changeback to leather in both professional practice andstudent training.Achievements to dateThe study is still underway – data collectiontakes approx. six months per patient. Currently15 patients are participating in the study andwe are required to have at least 40 for astatistically significant result. This still appearsachievable but will be slower than expected.Publications to the end of 2002Abstract submitted to Australian OccupationalTherapy Conference committee to presentfindings and analysis of the literature review andprogress with the project. Anticipate publishingthe systematic review component if possiblein 2003.Proteome analysis of breastcancer – $5,500The project team membersDr Kiron Bhatia, Surgical Trainee,Royal Hobart HospitalDr Roger Lord, Lecturer (Surgery),University of TasmaniaProfessor Peter Stanton, University of TasmaniaThe aim of the researchThe research seeks firstly to look at differencesin known biological markers of breast cancerbetween two populations of women, one groupfrom Japan and the other from Australia. Womenfrom Asian regions have a much lower mortalityrate for breast cancer when compared with thoseof industrialised nations like Australia. It has beensuggested that environmental and/or dietaryfactors may account for this observation but asyet there are no data to clearly indicate that thisis the case. If biological differences between thesegroups do exist then these might present ashigher or lower levels of known biological markersof the disease. The second part of the study usesa separation method that allows complexmixtures of molecules to be resolved. Using thismethod a biological map of all the molecules thatmake up a piece of tissue, such as a breastcancer, can be separated to produce a map whichis unique for that tissue. Normal breast tissuewould thus have a different map to breast canceror secondary cancers which have broken awayfrom the main tumour and begun to grow inanother region of the body. The differencesbetween maps for the normal breast tissuecompared with cancerous tissue may representmolecules which have been generated as a resultof the cancer. These molecules may be markersof the disease or targets for vaccines orpharmaceutical drugs.Achievements to dateThis study began in 2000 when the first breastcancer samples were beginning to be collectedfrom the local population. To date, threepopulations have been extensively sampled,which include local patients and patients fromGreece and Taiwan. The study revealed 80 (studyon-going) proteins that were unique to breastcancer and not found in normal breast tissue.In order to ‘screen out’ proteins from this setwhich might be known markers of breast cancer,an Honours student in 2002, Kylie Roberts, usedantibody elimination techniques on the set ofproteins to narrow down the search for whatmight be new diagnostic or pharmaceuticaltargets for breast cancer. Her Honours thesis titledProteomic analysis of prognostic factors ofbreast cancer has been completed and she hasnow joined the project team to continue this workas part of her PhD studies. This study has employedstate-of-the-art technologies in image analysis.The 2001 protein characterisation study wasdesigned to allow the purchase of a key softwareprogram to be used in this and future projects.Additional funding obtainedThe Paul Mackay Bolton Foundation Scholarshipin Cancer ResearchAnalysis of outpatient bonemarrow transplantation(BMT). A review of thepractice of conductingBMT on an outpatientbasis, rather than admittingpatients to hospital.Assessing the benefitsto the patients and to thehealthcare system – $4,400The project team membersDeirdre Tuck RN, Nurse Researcher,University of TasmaniaJane Anderson RN, Transplant Coordinator,Oncology Outpatients, Royal Hobart HospitalLouise Nicholson RN, CNM, Oncology Outpatients,Royal Hobart HospitalLeading researcherDr Roger Lord.18

The aim of the researchThis project reviewed the practice of conductingbone marrow transplantation on an outpatientbasis, rather than admitting patients to hospital.In the past this procedure was undertaken totallyas an inpatient, necessitating long weeks inhospital, away from the support of family andfriends. At the RHH, a few people havesuccessfully completed this treatment entirely inthe outpatient setting and many others have hadpart or most of the procedure carried out in thisway. We aimed to assess the benefits to patientsand the healthcare system of this practice.Achievements to dateWe have assessed the practice of conductingbone marrow and peripheral blood stem celltransplantation in the outpatient setting byretrospective review and an ongoing audit.Initially, ablative chemotherapy was commencedwithout hospital admission, then reinfusion ofautologous cells was also found to be feasible.At the RHH, patients now remain as outpatientsfor the entire process, being closely monitoredon the outpatient oncology ward, only beingadmitted if complications develop.Our results indicate that outpatient bone marrowand peripheral blood stem cell transplantationis both a feasible and safe initiative. As well asthere being a significant economic benefit for thehealth system of Tasmania, the outpatient approachis preferred by patients.Additional funding obtainedThe Cancer Council of Tasmania and the DavidCollins Leukaemia Foundation have supportedfurther analysis of bone marrow transplantationat the Royal Hobart Hospital.Publications to the end of 2002A paper is being prepared to be submittedto a peer-reviewed journal. We have presentedour results to fellow nurses and Professor RayLowenthal has presented these findings alongwith other supportive evidence at internationalconferences.B.G. Thomas BequestGrantBevis George Thomas died of Parkinson’s diseasein 1991, and made a generous bequest in his willfor research into the cause and treatment of thedisease. The BG Thomas legacy has enabled theestablishment of a dedicated research fund forstudies into Parkinson’s disease, with the firstthree year program commencing in 2001.a-Synuclein: a possibletherapeutic target forinhibiting theneurodegeneration ofParkinson’s disease– $99,000The aim of the researchStudies indicate that the abnormal processing ofthe alpha-synuclein protein contributes to thedevelopment of Parkinson’s disease. However,the developmental localisation and cellular roleof alpha-synuclein and the other members of thesynuclein protein family, beta- and gammasynuclein,remain contentious.The aim of our investigation is to determine thecellular localisation of alpha-, beta- and gammasynucleinin different cell types of the brain(cortical neurons, oligodendrocytes andastrocytes) in cell culture conditions. Theresponse of these cell types and the synucleinprotein to various forms of cellular injuryimplicated in Parkinson’s disease and otherdegenerative conditions will be the main focusof these studies.Achievements to dateWe have determined the cellular localisation ofalpha-, beta- and gamma-synuclein in immatureto mature cortical neurons and oligodendrocytesin culture. In addition, mature cortical neuronswere injured by cutting the bundles of axons thatconnect groups of cells in culture, with theirresponse to injury observed.This study has demonstrated that:• alpha- and beta-synuclein have preciselocations within cortical neurons, and theyare generally not overlapping in theirdistribution• synuclein proteins accumulate rapidly indamaged axons, as well as within regenerativestructures (termed neurites), indicating thatthey may actively be involved in axonalregeneration and repair• there is differential localisation of alpha-,beta- and gamma-synuclein in braincell types and cellular compartmentsAdditional funding obtainedData obtained in the preliminary stages of thisproject were used to support a successful applicationto the National Health and Medical ResearchCouncil for a project grant funding by ProfessorVickers and Dr Gai Wei-Ping (Flinders University ofSouth Australia). This three-year grant fundscomplementary studies on synuclein cell biologyas well as its abnormal modifications in Parkinson’sdisease (W.P. Gai, D. Poutney and J.C. Vickers‘Alpha-synuclein metabolism in humanneurodegenerative disease’, National Health andMedical Research Council – $380,000, 2002-2004).Dr James Vickers accepts the bequest funds fromB.G. Thomas’ sister-in-law Jeanette Roelvink.The project team membersProf. James Vickers, Head, Disciplineof Pathology, University of TasmaniaMarian Quilty, PhD student, PathologyDepartment, University of Tasmania19

Publications to the end of 20021. Quilty, M.C., W-P. Gai, D.L. Pountney,A.K. West, and J.C.Vickers. Localisation ofalpha-, beta- and gamma-synuclein duringneuronal development and alterationsassociated with the neuronal responseto axonal trauma. Exp.Neurol. in press.2. Quilty, M.C., Gai, W-P., Chuah, M.I., West,A.K., Vickers, J,C. Localisation of alpha-,beta-, and gamma-synuclein in neuron andoligodendrocyte cultures. Society forNeuroscience, Orlando,FL, 2002.Starter Grants– round 2Vascular access devicetracking tool – $3,800The project team membersPam Sykes, Infection Control Coordinator,Royal Hobart HospitalMelinda Griffiths, Clinical Nurse, InfectionControl, Royal Hobart HospitalThe aim of the researchA vascular access device tracking tool is to bedeveloped to ascertain accurate denominator datain order to provide a rate of infection associatedwith these devices. These data will be reported asinfections per 1,000 line days, consistent withinternational reporting methodology, and willprovide improved evaluation of RHH standardsof care relating to vascular access devices.Achievements to dateTo date, a comprehensive literature review anddraft data collection tool have been devised.Publications to the end of 2002It is intended that this project will be publishedin the Australian Infection Control Journal whencompleted.Prognostic factors in plasmacell disorders – $4,400The project team membersDr Elizabeth Tegg, Haematology Registrar, RHHMrs Sandra Heard, Scientist in Charge ofCytogenetics, RHHDr Katherine Marsden, Director of Pathology andHaematology, RHHThe aim of the researchTo determine the incidence of CD56 expressionand chromosome abnormalities, particularlychromosome 13, with prognosis in multiplemyeloma (MM) and in monoclonal gammopathyof unknown significance (MGUS).Achievements to dateDuring the course of this study, 20 new cases ofMM (19) or MGUS (1) occurred and were includedin this study. To date, all these samples have hadtheir CD56 expression on their plasma cells andconventional cytogenetics and F.I.S.H analysisperformed.A high rate of cytogenetic abnormalities has beenfound. Conventional cytogenetics found anabnormality rate of 26% and this is increased to54% with the use of F.I.S.H.. F.I.S.H. results implya higher incidence of monosomy RB-1 loci thanconventional cytogenetics, which may be ofclinical significance.CD56 expression is very high in myeloma patients,and variable in MGUS, and clinical follow-up willenable conclusions to be drawn about this. Wehave analysed the 20 diagnostic patients and thepresence of CD56 expression and cytogeneticabnormalities will be correlated with prognosisat a later date.This study has changed practice not only in theRoyal Hobart Hospital, but statewide, ascytogenetics and CD56 expression is routinelypreformed on all samples that relate to plasmacell disorders.Publications to the end of 2002Prognostic factors in plasma cell disorders:Elizabeth Tegg, Catherine Wren, Sandra Heard,Beth Rees and Katherine Marsden. Departmentof Pathology, Royal Hobart Hospital, Hobart,Tasmania, RCPA update course.Erythrocyte autoimmunitygenerated followingcardiopulmonary bypasssurgery – $4,400The project team membersDr WY Yeo, Surgical Trainee,Royal Hobart HospitalDr Roger Lord, Lecturer (Surgery),University of TasmaniaProf. Peter Stanton, Professor of Surgery,University of TasmaniaThe aim of the researchPatients who undergo bypass surgery are placedon a pump to carry out circulation while theprocedure is undertaken. The effect of beingplaced on this pump results in damage to someof the body’s red blood cells and activation of theimmune system. Normally, the immune systemwould not mount a response against a cell, whichis part of the human body, however when a cellis damaged, parts of that cell may displaymolecules which would not normally be recognised.It is thought that the immune system in turnmounts a response by producing antibodiesagainst these, preventing other red cells fromfunctioning. As a result the body may not getenough oxygen and breathing may becomestrained. The response takes about two weeksto peak, which is approximately the time whenpatients who have had bypass surgery oftencomplain of breathlessness. The aim of thisstudy is therefore to confirm whether or notauto-antibodies are being generated andif this accounts for breathlessness.Achievements to dateA group of 20 patients has so far been examinedfor evidence of red cell autoimmunity followingbypass surgery. In each case patients who hadbypass surgery also had antibodies against bothregions of the surface and cytoplasm of red cells.The project is to be furthered in 2003 by Roy Kwan20

(4th year medical student) who presented a thesistitled Erythrocyte autoimmunity following onpumpcompared to off-pump coronary bypasssurgery. Roy also incorporated lung function testsinto the study, which showed that a significantdecrease in alveolar volume occurred between day14 and lung capacity following surgery. Furtherexamination of the lung function following bypassis now planned for future studies. A publication onthe work is currently in progress.Additional funding obtainedUniversity of Tasmania – Institutional Research GrantRole of the AP-1 transcriptioncomplex in lipid-induceddifferentiation of leukaemiacells – $5,500The project team membersMs Joanna Burrows, Research Scientist, OncologyLab, University of TasmaniaMs Olivia McQuestin, BSc (Hons) student,Oncology Lab, University of TasmaniaDr Scott Ragg, Senior Scientist,Stem Cell Transplant Laboratory, RHHThe aim of the researchThis study built upon the findings of a RHHResearch Foundation Starter Grant awardedin 2000. An alternative approach to treatingleukaemia is to trigger the cancer cells to matureinto cells that are unable to divide and eventuallydie. We had shown previously that the naturallyoccurring lipid, ceramide, causes growth arrestand terminal differentiation in leukaemia cells,which is associated with expression of the c-fosand c-jun regulatory genes. Together c-Fosand c-Jun form the AP-1 transcription complexthat proceeds to activate other genes. Anunderstanding of the roles of AP-1 in forcedgrowth arrest and terminal differentiation willprovide a better understanding of the potentialfor ceramide in the treatment of leukaemia.Achievements to dateWe had shown that leukaemia cells inducedto differentiate by treatment with ceramide hadincreased levels of the c-jun mRNA and protein.Preincubation of the leukaemia cells with aneutralising (antisense) oligo complementaryto the c-jun mRNA blocked the ceramide-inducedincrease in the c-jun protein, thus preventing theformation of the AP-1 transcription complex.Importantly, this blocking of c-jun expressionand prevention of AP-1 formation also preventedthe ceramide-induced differentiation of theleukaemia cells. This study thereforedemonstrated that ceramide signalling utilisesthe c-jun gene and AP-1 transcription complexin order to force leukaemia cells to mature intoa non-dividing cell. These results mean that wenow know that ceramide works, at least in part,by changing the expression of genes inside aleukaemia cell and that we should endeavourto determine what other genes are involved.Margie and Alan Bryce of Fern Tree take delivery oftheir raffle prize – a brand-new Holden Astra!Publications to the end of 2002The role of c-Jun and c-Fos in ceramide-inducedmyeloid differentiation. Thesis submitted byOlivia McQuestin for Bachelor of Science withHonours, University of Tasmania 2001 (AwardedFirst Class Honours)Confirmation of alteredgene expression interminally differentiatinghuman leukaemia cells usingReal-Time RT-PCR – $5,500The project team membersCharles Connor, PhD student,Oncology Lab, University of TasmaniaMs Sandrine Chopin, Research Scientist, OncologyLab, University of TasmaniaDr Scott Ragg, Senior Scientist,Stem Cell Transplant Laboratory, RHHThe aim of the researchThis study built upon the findings of a ResearchFoundation Starter Grant awarded in 2000. Ourlaboratory is studying the genetic mechanisms thatcause immature, aggressively growing leukaemiacells to mature into non-dividing ‘adult cells’that eventually die, a process called terminaldifferentiation. We used a filter array dotted withover 1,100 cancer specific genes to try and determinethe genes that are turned on or off followingtreatment of leukaemia cells with ceramide, asubstance that we have shown to cause terminaldifferentiation. Having identified a number of genesthat are possibly regulated by ceramide, we neededto confirm the differences in gene expression usinga very sensitive method called Real-Time RT-PCR.This will provide information about the processeswithin a cell and may allow us to identify differentapproaches to treating leukaemia.Achievements to dateThis project first required the development of arelatively new technique called Real-Time RT-PCRthat allows us to quantitatively compare the level ofexpression of a gene in two different samples. In thiscase the samples were i) leukaemia cells treated withAdditional funding obtainedRHH Research Foundation 2001 Major ProjectGrant: Identifying the genes that halt the growthof leukaemia cells21Jill Perryman – special guest speaker at theDecember 2000 Christmas breakfast.

ceramide and ii) untreated leukaemia cells. We hadused a filter array to compare the expression levelsof genes in these two samples and, after identifyinggenes whose expression had been changed, weneeded to independently confirm these changeswere real by using Real-Time RT-PCR. This projectindependently confirmed that ceramide was alteringthe expression of genes in leukaemia cells and thisprovided the ‘proof of principle’ for us to embarkon a major investigation of the genetic changes thatwere occurring in these cells.Additional funding obtainedRHH Research Foundation 2001 Major ProjectGrant: Identifying the genes that halt the growthof leukaemia cellsPublications to the end of 2002The mechanisms of ceramide-induced terminaldifferentiation of myeloid leukaemia; Doctoralthesis being prepared by Charles Connor,University of TasmaniaMazda FoundationGrantsThrough a generous donation from the MelbournebasedMazda Foundation, the Research Foundationwas able to fund an additional round of grants fornew researchers during 2001.QAH Physiotherapy –Abdominal muscleassessment during and afterpregnancy – Part 4 – $4,400The project team membersHeather Gouldthorpe, Manual HandlingCo-ordinator, Royal Hobart HospitalJanet Millner, Manager of Physiotherapy Services,Royal Hobart HospitalSarah Tan, Acting Senior Physiotherapistin Women’s Health, RHHChitra Harris, Physiotherapist in Women’s Health, RHHThe aim of the researchThe project is testing the hypothesis that a gentleabdominal exercise program in pregnancy willlower the incidence of• abdominal muscle separation in pregnancy• stress incontinence and other pelvic floorproblems, both during and after pregnancy• low back pain during pregnancyAchievements to dateIt was hoped to recruit 130 women into the projectand it was anticipated that this would take two tothree months. We started recruiting women intothe project in early 2002 and, by 14 August 2002,104 women had been recruited. (There arecomparatively low numbers of primiparous womennow presenting to the QA Maternity Servicesat the RHH – presumably because of the FederalGovernment policy on private health insurance.)We decided on 14 August to cease recruitingpatients due to the time factor. We are continuingto follow-up the majority of subjects at 28 weeks,36 weeks and at birth. As at 14 August at least 18subjects who were recruited to the project andrandomised to the exercise group failed to turnup to appointments to be taught abdominalexercises, and others in the exercise group havewithdrawn from the project. In addition, twosubjects who were in the exercise group haveadmitted to doing no exercise when they werefollowed-up at birth. Post-partum follow-up ofsubjects at six weeks is due to commence soon,with analysis of the data to follow.Determination of theprevalence of malnutritionin general adult in-patientsat the Royal Hobart Hospital– $4,400The project team membersJenny McKerchar, Senior Dietitian, Nutritionand Dietetic Service, Royal Hobart HospitalJean Symes, Manager, Nutrition and DieteticService, RHHDr David Woodward, Senior Lecturer,Biochemistry, University of TasmaniaThe aim of the researchThis project aimed to evaluate the nutritionalstatus of a sample of adult in-patients from avariety of wards at the Royal Hobart Hospital(RHH), and hence provide a cross-sectionalestimate of the prevalence of malnutrition amongthese patients. The study used the SGA, a validand reliable nutritional assessment tooldeveloped by Detsky et al 1987.This study will provide the first quantitativemeasure of malnutrition among public hospitalpatients in southern Tasmania and will contributeto the limited pool of data on the prevalence ofmalnutrition in Australian hospitals. This studywill provide baseline data for future comparisons,and for evaluation of interventions such asnutrition screening. Nutritional screeningallows early identification and prioritisation ofmalnourished patients so nutrition support canbe provided, aimed at improved health outcomes.Achievements to dateNine assessors were trained over a period of threemonths, and a pilot study was undertaken in April2002 to test inter-assessor reliability in using theSGA tool. Assessments of a total of 238 patientswere completed on five nominated collection daysin May 2002. Relevant laboratory data were alsoobtained for the majority of these patients. A dataentry clerk was employed for two weeks in July,and entered all the data on spreadsheets.The team is now in the process of analysing the dataand writing up the findings for the RHH, and forsubmission to a professional peer-reviewed journal.Relocation for medicaltreatment: Impact onpatients and families andimplications for deliveryof health services – $4,400The project team membersJanet Whelan, Manager Social Work Services,Royal Hobart HospitalBill Folkerts, Social Worker, Royal Hobart HospitalMargaret Dugon, Social Worker, Royal Hobart HospitalMichael Johns, Mazda dealerprincipal, presents the MazdaFoundation grants in 2001.22

The aim of the researchThe aim of this project was to learn directly frompatients and their carers about the experienceof travelling away from their homes for medicaltreatment that was not available to them locally.Anecdotal information obtained by social workersin their practice suggested that, for somepatients, relocation was a disruptive and costlyexperience.The researchers aimed to usequalitative research methods to identify significantissues for patients and families and to makerecommendations regarding policies and deliveryof health services, including appropriate pointsfor social work referral and intervention.Achievements to dateTwo focus groups have been conducted followedby 22 interviews with patients and carers. Thecontent of the interviews is currently beinganalysed. Early indications are that the mostsignificant comments from the participants willrelate to two areas: the practical and emotionalsupport provided by carers when patients travelfor treatment (to the extent that many patientsreport that they could not have faced theexperience without the involvement of the carer),and the pivotal role of the Patient TransportCoordinator in making reliable and timely travelarrangements and providing appropriateinformation about accommodation and othernon-medical services that patient and carer mayrequire when they are away from home.Other factors emerging include the adversefinancial impact of incidental expenses incurredby the patient and family, and the importanceto the patient of receiving good information fromall parties involved about what to expect intreatment at the receiving hospital and when thepatient returns home. With a few exceptions,most participants have commented favourablyon the level of information received from doctorsat home and in the receiving hospital.2002Major GrantsThe role of pro and antiinflammatorycytokinesin the progression ofmultiple sclerosis andthe occurrence of multiplesclerosis relapses – $10,000This MS project was funded by the ResearchFoundation, which was matched in itscontribution by Hobart’s Luttrell family,which had been particularly affected by multiplesclerosis, and wanted to make a donation toresearch into the causes and treatment of thedisease in memory of Mr Joe Luttrell.The project team membersDr Bruce Taylor, Head of Neurology,Royal Hobart HospitalDr Fotini Pittas, MS Researcher, Royal Hobart HospitalProf. Haydn Walters, Professor of Medicine,University of TasmaniaThe aim of the researchThis project aims to measure the pro and antiinflammatorycytokines in MS. Based on the theorythat MS is associated with the development on a Th1driven (pro-inflammatory) cytokine milieu. Thistheory although widely held has not been proven.Achievements to dateWe have established cytokine assays for IL12, IL10,IL4, TNFα, and TGFβ, using stimulated PBMCs frompatients and controls. We have been able to measurelevels of cytokines in serum and from PBMCs inpatients and controls. We have been able toreproduce results and have proven our laboratorytechniques. We are currently working on largernumbers of patients and controls and have submittedan NHMRC grant application based on thepreliminary work and establishment of assays madepossible by the grant. This work is still ongoing.Identifying the genes thathalt the growth of leukaemiacells – $13,000The project team membersMs Joanna Burrows, Research Scientist, OncologyLab\oratory, University of TasmaniaDr Scott Ragg, Senior Scientist,Stem Cell Transplant Laboratory, RHHThe aim of the researchThis study built upon the findings of a ResearchFoundation Starter Grant awarded in 2001. Manycancers arise due to defects in the turning on oroff of genes that are important in controlling cellgrowth. Finding reagents \to fix incorrect geneexpression is the next frontier in cancer drugdevelopment. Ceramide, a signalling moleculewithin the body, causes activation of tumoursuppressor genes, which stop leukaemia cellsfrom growing, resulting in cell maturation andeventual death of the cancer cell. By determiningwhich genes are turned on or off by ceramide wemay identify a novel therapeutic approach forleukaemia treatment.Achievements to dateThis major project is currently ongoing. To date,we have become the first Tasmanian laboratoryto perform a new genetic technique calledMicroarray Screening. Traditional molecularbiology methods only permit the study of fewindividual genes at one time, thus limiting thethroughput of the procedure and making the‘whole picture’ of gene function hard to obtain.Microarray Screening allows the expressionanalysis of thousands of genes simultaneouslyand is the technique we are using to examineceramide-induced gene expression in leukaemiacells. The Microarrays we have performed to dateare indicating that a key family of growth controlgenes is being re-activated in leukaemia cellstreated with ceramide. Unravelling the controlmechanisms of these genes may provide newstrategies for leukaemia treatment.23

Factors affecting therehospitalisation of patientswith schizophrenia at the RoyalHobart Hospital – $18,000The project team membersDr Brett Daniels, Intern, Royal Hobart HospitalDr Philip Reid, Consultant Psychiatrist,Dept. Psychological Medicine, RHHProfessor Ken Kirkby, Professor of Psychiatry,University of TasmaniaDr Milford Macarthur, Consultant Psychiatrist,Dept. Psych. Medicine, RHHThe aim of the research• To determine the rate of rehospitalisation forpatients with schizophrenia admitted to theDepartment of Psychological Medicine at theRHH between 1991 and 1999 and compare thisto previously published rates from the 1980s.• To identify factors that may have affectedchanges in rehospitalisation rates sinceearlier research.Achievements to dateIt has been found that rehospitalisation rates forschizophrenia and other psychiatric disorders,including major depression and bipolar disorder,are lower than those reported by the authors fiveyears ago. There have been a number of changesto the treatment of these disorders in the localcommunity since the previous study, both in termsof medication and in hospital services. Furtherresearch will be conducted to investigate the effectof these changes on the rehospitalisation rate.Tasmanian Epilepsy RegisterHealth Study – $12,500The project team membersProf. Terry Dwyer, Menzies Centre for PopulationHealth ResearchDr W D’Souza, MelbourneDr B Taylor, Head of Neurology,Royal Hobart HospitalThe aim of the researchTo establish an epilepsy register in Tasmaniato investigate the longitudinal health outcomes(physical, psychiatric, health utilisation andquality of life) of a community cohort of peoplewith epilepsy, and assess potential explanatoryfactors that may improve these outcomes.Although the overall priorities of The EpilepsyRegister are longitudinal, the current applicationis confined to the baseline data collection andanalysis. The baseline survey is specificallydesigned to have the statistical power to answerseveral important research objectives:1. The prevalence of different epilepsysyndromes (based on the InternationalLeague Against Epilepsy Classification) in acommunity sample of people with epilepsy2. Do people with epilepsy in the communityhave a high prevalence of seizure-relatedinjuries (burns, head injuries, dental,fractures, submersion and motor vehicleaccidents) and the relationship, if any,between seizure type frequency and epilepsysyndrome?3. Do people with epilepsy in the communityhave a high prevalence of co-morbidities(intellectual, developmental, physical andpsychiatric) and the relationship, if any, withseizure frequency, age at onset, epilepsysyndrome and anticonvulsant medication?4. Do people with epilepsy in the communityhave high utilisation of health servicesand which services are they using?No such community-based, prospective, registerof epilepsy has been established anywhere in theworld and therefore the findings from this studywould have major international as well asAustralian significance.Achievements to dateRecruitment to the register commencedin September/October 2002.Characterisation of theimmunosuppressive protein(LSF-1) – $15,000The project team membersDr Roger Lord, Lecturer (Surgery),University of TasmaniaProf. Peter Stanton, Professor of Surgery,University of TasmaniaThe aim of the researchTransplantation is used to replace organs forpatients with failure of kidney, heart, liver, lungand pancreas. The major barrier to successfultransplantation in all patients is the host immunesystem rejecting the graft. However, livertransplantation is less susceptible to all forms ofimmunologic events including hyperacute, acuteand chronic rejection and also graft-vs-hostreaction (GVHR). In certain strains of mouse, ratand pig, the allografted liver is accepted withoutusing any immunosuppressive treatment on therecipient. A better understanding of themechanisms underlying this immunologicprivilege rendered by liver transplantation wouldpotentially yield insights and strategies thatcould be applied to other organ transplants.The researchers have identified and partlycharacterised an immunosuppressive proteinin the serum of liver-transplanted rats, whichis novel and has been designated as liversuppressor factor one (LSF-1). LSF-1 is highlyimmunosuppressive both in cell culture assays andwhen tested in animals. This study aims to furthersequence the molecule, map its suppressive siteand characterise the cells that produce themolecule. LSF-1 has potential for development as anovel diagnostic tool to determine when tolerancehas been attained following liver transplantationand may also have potential as a pharmaceuticalto combat rejection in other organ transplants andfor treatment of autoimmune diseases.Achievements to dateThe LSF-1 project has moved slowly ahead withone new publication pending in 2003 betweengroup collaborators in Brisbane and Taiwan. Thispublication looks closely at the pathways at whichDr Brett Daniels.24

LSF-1 may act on to prevent organ rejectionfollowing transplantation. Further sequence datahave also been obtained for the molecule butfurther work is needed to obtain the full sequenceof this important protein. The project hasgenerated much initial commercial interest andis currently being examined for development forboth diagnostic and pharmaceutical usage.Identification of genescausing congenital cataract– $15,000The project team membersProf. Simon Easteal, Dr J Dickinson andDr Jamie Craig, Centre for Eye Research Australia,University of Melbourne and Kathryn BurdonThe aim of the researchThe aim of this project is to identify genesresponsible for congenital and paediatric cataractin the south-eastern Australian population. Ourfirst priority is to confirm suggestive linkages toseveral known cataract loci in four large familiesby the genotyping of additional micro-satellitemarkers in the regions. Haplotype analysis will beused to refine the regions of linkage and we screenpotential candidate genes in refined regions formutations segregating with disease phenotype.Following the detection of novel disease-causingmutations, we plan to screen our large collectionof families to determine the prevalence of themutation in this population. Cataract is a conditionin which the lens of the eye becomes opaque, whicheventually affects vision and can lead to blindness.It generally affects people over the age of 60 as theeye ages, but is also found in a hereditary formin children, usually referred to as congenitalor paediatric cataract.We are attempting to discover new genes thatcause this hereditary form in a collection offamilies from both Tasmania and Victoria. Thisyear has seen the beginning of the laboratorywork for this project following the collection ofDNA samples from over 50 families across the twoStates. The first stage of this project is to screenour family collection of the genes already knownto cause cataract in order to eliminate familieswith known mutations from the search for novelgenes. This is well underway with five genesalmost completed.This work has shown a previously reportedcausative mutation is present in one largeVictorian family. Once this task has beencompleted for the remaining known cataractgenes, families without an identified mutationwill be used to search for new genes that areinvolved in the disease.Achievements to dateLinkage has been detected to candidate genes intwo of the large families. Subsequent sequencingof these genes has elucidated the causativemutations in both families. Further genotyping ofthe remaining families is continuing. In addition,linkage has been detected on the X-chromosomein a large family with an X-linked form. The regionhas been refined by fine mapping and knowngenes in the region sequenced. Work is continuingon the search for novel genes in the region.Additional funding obtainedOphthalmic Institute of Australia and an RHHResearch Foundation Starter Grant 2000Clinical validation ofTasmania’s salmonid industrydiving decompressionschedules by Dopplerassessment of decompressionstress – $15,000The project team membersDr. D. Smart, C. Van den Broek, M. Walker,C. Baines, D. Lacey, D. Eastman and R. Nishi;Diving and Hyperbaric Medicine Unit, RHHThe aim of the researchOver the past 12 years, the Diving and HyperbaricMedicine Specialists at the RHH have contributedsignificantly to the development of safedecompression tables and diving practices inTasmania’s flourishing salmonid aquacultureindustry. The resultant decompression scheduleshave produced a 98% reduction in the incidenceof decompression illness since 1990, preventing45 divers per annum from contractingdecompression illness (potentially preventingup to 200 hyperbaric treatments at RHH). Currentsalmonid aquaculture dive schedules werederived empirically, but have not been clinicallyvalidated using ‘gold standard’ DCIEM Dopplerbubble detection methods. The technology andskills are now available to undertake thisvalidation at the RHH Diving and HyperbaricMedicine Unit.This study plans to commence final Dopplervalidation of the salmonid aquaculture industry’sunique diving schedules, to confirm their statusin line with world’s best practice, and to followup previous research undertaken in the 1980sand 1990s.Achievements to dateField data collection has been completed fromthe first of five salmon farms, and we are nowcommencing our second field site. It is too earlyand numbers are too small to provide anyinterpretation of data at this time.PhD student Kylie Roberts analyses imagesat the University’s Medical School usingRHHRF-funded equipment.25

Molecular identificationand characterisation of miniP-glycoproteins – $15,000The project team membersDr C M Trambas, Research Fellow,University of TasmaniaDr G M Woods, Senior Lecturer, Disciplineof Pathology, University of TasmaniaThe aim of the researchThe priority of this research was the molecularidentification and characterisation of mini P-glycoproteins, two novel molecules which we havediscovered in human haematopoietic cells. Ourdiscovery of these proteins was facilitated by thesimilarity to P-glycoprotein, the multi-drugtransporter. P-glycoprotein has been extensivelystudied in cancer because it causes multi-drugresistance thereby allowing cancers to withstandchemotherapy. The main aim of this project wasto characterise the genetic identity of mini P-glycoproteins.Achievements to datePurified DNA sequences of this mini P-glycoproteinhave been produced using various molecularbiological strategies to amplify small fragmentswhich represent key parts of the protein. We arecurrently in the process of analysing a numberof these sequences but to date the informationreceived has not been as informative as initiallyexpected.Additional funding obtainedFurther applications have been made, as thisproject is still ongoing and there are still fundsremaining which will allow the work to becontinued. It should be noted that a similar grantwas submitted to the David Collins LeukaemiaFoundation to pay for the salary componentof this research.investigate the reasons why some cytokines causeantigen-presenting cells to induce suppression,which may allow tumours to escape immunedetection. The main aim of this project was toexpand our recent work where we had discoveredthat IFN-γ is not produced in mice treated withcarcinogens. We have also discovered that theIL-12 p40 cytokine is also altered in carcinogentreatedmice. As dendritic cells play a critical rolein the initiation of various immune responses, andas IFN-γ and IL-12 p40 act on dendritic cells, wepropose that an alteration in the production ofthese cytokines can result in immune suppression.Achievements to dateInitial aspects of the study concentrated on therole of IFN-γ. We discovered that even thoughIFN-γ was not produced, it did not have thecritical role in immunosuppression as would havebeen predicted. By supplementing in vitrocultures with IFN-γ there was still a failure toinduce T cell proliferation. If IFN-γ was the onlycytokine involved in inducing proliferation and,as its absence was apparent from carcinogentreatedmice, it would have been predictedthat by replacing cytokine the immune responsewould be returned to normal. This was notthe case and therefore indicates thatimmunosuppression occurs as an event eitherbefore the production of IFN-γ or more likelyas a downstream effect of IFN-γ.Additional funding obtainedA successful application was submitted to theCancer Council of Tasmania for funding in 2003.Publications to the end of 2002The project has been published as aBMedSc(Hons) thesis of Caroline Airey.Analysis of reduced IFN-γand increased IL-12 (p40)as a mechanism contributingto carcinogen inducedimmunosuppression – $12,000The project team membersDr Greg Woods, Senior Lecturer, Disciplineof Pathology, University of TasmaniaProfessor Emeritus H Konrad Muller,Discipline of Pathology, University of TasmaniaDr Zemin Wang, USAThe aim of the researchCancer can develop when tumours escapedetection by the immune system. The immunesystem contains a population of antigenpresentingcells that initiate the immune responseand, in the presence of cytokines, cause tumourdestruction. In the presence of the ‘wrong’cytokines we propose that antigen-presentingcells cause suppression. Our proposal will26

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