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HRC news

Issue No. 80 December 2013

INSIDE

Door opens to new fertility treatments Otago researchers’ discovery offers hope for infertile couples. Find out more on page 16.

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Anaemia in the womb affects heart health as an adult By Suzy Botica

FetalAnaemiaStudy

Adults who developed a low haemoglobin level (anaemia) in their mothers’ wombs may be at greater risk of heart problems, according to a ground-breaking study led by paediatrician and HRC Clinical Research Training Fellow Dr Alexandra Wallace.

The HRC-funded study measured the heart function, coronary blood flow and cardiovascular risk factors of adult survivors of severe rhesus haemolytic disease in New Zealand.

Rhesus disease occurs when antibodies in a pregnant woman’s blood destroy her baby’s red blood cells leading to the baby developing anaemia.

Just over half of the study’s 187 participants received an intrauterine blood transfusion to treat their rhesus disease-induced anaemia at National Women’s Hospital in

Auckland between 1963 and 1992. For comparison, the rest of the study participants were made up of their siblings who did not have rhesus disease. The participants’ ages ranged from 18 to 47, with an average age of 37.

The study is the first to look at the effects of anaemia in the womb and treatment with intrauterine blood transfusion on adult heart health.

“The number of heart cells you have when you’re born is essentially the number you have for life. Fetal anaemia exposes the developing heart to physiological stress, which may alter the replication and differentiation of these cells before birth,” says Dr Wallace.

The results from this study provide the first evidence that babies who have anaemia in the womb may have permanently altered heart structure and function – changes that could potentially have lifelong health consequences.

“Using cardiac MRI, we found that the participants who had anaemia in utero had smaller and thicker walled left ventricles than their unaffected siblings,” says Dr Wallace. “They also had lower levels of high-density lipoprotein (or HDL, the so-called ‘good cholesterol’) and increased sympathetic control of heart rate variability, both of which suggest increased cardiovascular risk. In addition, analysis of coronary blood

flow at rest and with stress indicates that exposure to anaemia before birth may also impair coronary blood vessel function.”

Despite these differences, Dr Wallace says all findings for those exposed to anaemia before birth were within normal limits, so the absolute increase in cardiovascular risk for these individuals is likely to be very small at their current age. “Further review in 10 to 20 years’ time will help establish if they have earlier onset or more severe cardiovascular disease in later life.”

Dr Alexandra Wallace with her sons Lachie (4), on the left, and Sam (3)

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HRC News December 2013

Health Research Council of New ZealandTe Kaunihera Rangahau Hauora o Aotearoa

Chief Executive’s messageAs I write this message there is less than a month before Christmas. It is still a busy time for us at the HRC, as we have many funding opportunities in process.

The 2014 funding round has taken several steps forward since the last issue of HRC News. All proposals are now undergoing peer review, prior to being considered by assessing committees in the New Year.

The HRC estimates the total value of proposals to our annual funding round this year to be about $475 million. We will be able to support about $65–70 million of contracts. For the five types of contract offered in the 2014 round, we will likely fund six Feasibility Studies (out of 31 applications), 10 Emerging Researcher First Grants (out of 44 applications), 4–5 Programmes (out of 15 submitted), 3 Explorer Grants (from 24 submitted) and about 30 Projects (from an initial 351, 100 of which were selected to put forward full proposals).

The number of Explorer Grant applications is markedly down from the 116 received last year, which indicates that applicants are now more aware of the special requirements for this particular fund.

I want to thank all involved in the annual funding round, including the researchers who spend a great deal of time planning and preparing their applications, research office staff, our very dedicated peer reviewers, and the HRC Secretariat for making the process run as smoothly as possible.

We recently announced our Career Development Award recipients for 2014. These awards are a fantastic opportunity to help some of New Zealand’s best and brightest become world-class leaders in their fields.

We also awarded our Liley Medal to Professor Michael Baker from the University of Otago, Wellington, at the Royal Society of New Zealand’s Research Honours event last month. Through his research Professor Baker and his colleagues have challenged the widely held view that as a country gets wealthier, infectious diseases inevitably decline. You can read more about Professor Baker’s research in this issue of HRC News.

Finally, I wish all our readers a restful and enjoyable Christmas break.

Meri Kirihimete ki a koe me te whanau.

Dr Robin Olds Chief Executive Health Research Council of New Zealand

HRC Chief Executive, Dr Robin Olds

IN THIS ISSUE

Upcoming closing dates 3

Professor receives Liley Medal for revealing NZ’s dramatic rise in infectious diseases

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$1.2m high blood pressure trial funded

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2013 New Zealand Research Honours Awards

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Royal College honours top Kiwi paediatrician

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Virus particles set to help fight cancer

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Study identifies significant gaps in Māori maternal health knowledge

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Low blood sugar in newborns – how low is too low?

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Secretariat staff news 11

Curing the incurable: exploring a new protein replacement therapy

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Injury researcher wins national leadership award

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Licence policy drives research 14

‘The eyes have it’ in top health research Career Development Awards

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Key to brain’s role in fertility identified

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Subscribing to HRC NewsCurrent and past issues of HRC News can be viewed on the HRC website: www.hrc.govt.nz.

If you would like to subscribe to HRC News, please email: [email protected], and put ‘Subscribe HRC News’ in the header. Please include your name and postal address details. You can also use this email address to advise us if you no longer wish to receive HRC News.

Upcoming closing datesFor an up-to-date list of all application registration, opening and closing dates, please go to the HRC website: www.hrc.govt.nz.

Ngā Kanohi Kitea Full Project GrantOnline registration closes on 17 December 2013 (12pm)

Applications close on 11 March 2014 (12pm)

Hard copies of full project applications are due at the HRC by 14 March 2014 (5pm)

Dr Wallace also carried out a pilot study in sheep to help establish whether babies born preterm, who frequently become anaemic after birth, show similar changes to their heart structure and function as those who had anaemia in utero.

Almost all babies born preterm will become anaemic at some point, a condition known as anaemia of prematurity.

For the pilot study, anaemia was induced in sheep delivered preterm. This resulted in no long-term growth impairments, but these animals did have increased levels of haemoglobin in their blood as adults. There was a similar increase in haemoglobin levels in the anaemia-affected participants from the human study.

“This is a completely novel finding. We suspect that the cardiovascular changes as a result of anaemia have caused the body’s haematological system to undergo changes too. It might be the body’s way of trying to improve cardiac performance. The similarity of this finding in humans and sheep leads us to wonder whether anaemia before term equivalent age, whether experienced in- or ex utero, may have similar long-term health consequences.”

Further work by other members of Dr Wallace’s team is now underway to investigate the effects of anaemia following preterm birth on long-term heart structure and function.

Dr Wallace completed this study as part of her PhD at the University of Auckland’s Liggins Institute under the supervision of Distinguished Professor Jane Harding and Dr Stuart Dalziel. She would like to acknowledge the support of her collaborators, including Professor Brett Cowan and Associate Professor Alistair Young (Department of Anatomy with Radiology, University

of Auckland) who performed the cardiac MRI scans and complex coronary blood flow analysis; Associate Professor Ian LeGrice and Professor Bruce Smaill (Auckland Bioengineering Institute); Auckland cardiologist Dr Nigel Lever; and Professor Kent Thornburg from the Oregon Health & Science University in the US.

Information: Dr Alexandra WallaceLiggins Institute, the University of Auckland ✆ +64 021 628 [email protected]

One News presenter Wendy Petrie presents Dr Wallace with the prize for first place in the University of Auckland’s Exposure competition, an annual university-wide competition to showcase postgraduate research. Photo courtesy of the University of Auckland.

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Professor receives medal for revealing NZ’s dramatic rise in infectious diseasesThe HRC’s prestigious Liley Medal was awarded to Professor Michael Baker at the New Zealand Research Honours Dinner held in Dunedin on 27 November 2013. Sir William Liley’s widow, Lady Margaret Liley, was again able to present the Liley Medal, along with the HRC’s Board Chair, Mr Robert Stewart, ONZM, on behalf of the HRC.

Professor Baker, from the University of Otago, Wellington, has been honoured for his outstanding contribution to the health and medical sciences in the field of public health.

In 2012, Professor Baker was the lead author on an already highly cited paper1 in the world’s leading general medical journal, The Lancet. The paper presented a national study of 5 million overnight hospital admissions showing a dramatic rise in the incidence of serious infectious diseases and rising inequalities across populations in New Zealand.

The paper uncovered a relative increase of 51 per cent in the age-standardised rate of hospital

admissions for infectious diseases between the periods 1989–1993 and 2004–2008. The authors also showed that Māori and Pacific people and those who are socioeconomically disadvantaged bore a disproportionate share of the burden.

“Through this study Professor Baker and his colleagues have challenged the widely held view that as a country gets wealthier, infectious diseases inevitably decline. Instead, they’ve shown that in New Zealand we’re experiencing a double whammy, with a rise in infectious diseases as well as chronic diseases such as cancer and diabetes,” says the HRC’s Chief Executive, Dr Robin Olds.

“The findings have enormous

implications for health and social policy in New Zealand, and will likely stimulate research and action in other countries where ethnic and socioeconomic inequalities may predispose vulnerable populations to poor health outcomes.”

Information: Professor Michael BakerUniversity of Otago, Wellington✆ +64 4 918 6802 [email protected]

1 Dr Michael G Baker MBChB, Lucy Telfar Barnard PhD, Amanda Kvalsvig MBChB, Ayesha Verrall MBChB, Jane Zhang MSc, Michael Keall PhD, Nick Wilson MBChB, Teresa Wall DPH, Prof Philippa Howden-Chapman PhD (24 March 2012). Increas-ing incidence of serious infectious diseases and inequalities in New Zealand: a national epidemio-logical study, The Lancet, Vol. 379, Issue 9821, p1112-1119.

Professor Michael Baker receives the Liley Medal from Lady Margaret Liley and HRC Board Chair Mr Robert Stewart at the 2013 New Zealand Research Honours Dinner.Photograph courtesy of the Royal Society of New Zealand

Professor Michael BakerPhotograph by Dionne Ward

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About the Liley Medal

Liley Medal obverse Liley Medal reverse

The Liley Medal is awarded annually by the Health Research Council of New Zealand to recognise an individual whose recent research has produced a significant breakthrough within the health and medical fields. The medal is named after Sir William (Bill) Liley KCMG, BMedSc, MB, ChB, PhD (ANU), Hon. DSc

(VUW), Dip Obs, FRSNZ, FRCOG, Hon. FACOG (1929–1983), whose contributions to medical science, particularly obstetrics, while working at National Women’s Hospital in Auckland are still celebrated today. One of Sir William’s great contributions was to extend the use of spectrophotometry of amniotic fluid to a much wider range of potentially affected pregnancies – work which gained him an international reputation. The technique he developed made it possible to identify which baby could be safely in utero for a normal gestation period and which baby should be delivered.

For more information about the Liley Medal and Sir William Liley, go to the HRC website: www.hrc.govt.nz/news-and-publications/medals.

$1.2m high blood pressure trial fundedA $1.2 million nationwide project will evaluate how care for people with resistant high blood pressure1 can be improved in New Zealand. The project will comprehensively assess aspects of health delivery for people with high blood pressure.

A key part of the two year project will be a trial that will compare the effectiveness of a comprehensive clinical management approach with a new treatment that ‘zaps’ nerves to the kidney to reduce blood pressure.

The University of Auckland will lead this research, working with a large team of health professionals from across the country.

The trial will include several hundred people with resistant high blood pressure from throughout Auckland, Waikato and Christchurch.

The funding for the programme comes from the new Health Innovation Partnership that was established earlier this year between the National Health Committee and the HRC.

The five district health boards in Auckland, Waikato and Christchurch are supporting the trial.

New Zealand Chair of the Cardiac Society of Australia and New Zealand Professor Ralph Stewart says renal

denervation is a very promising technique, but its role in New Zealand health care is currently uncertain. Renal denervation is still new in this country and is only available in certain centres.

This trial will provide detailed, comprehensive advice for New Zealand on the optimal ways to help people with resistant high blood pressure. The trial itself, within this wider programme of work, will compare the effects of renal denervation to those of intensive medical management on blood pressure and other measures of health.

The trial will be clinically led, with strong participation from medical and interventional specialists and general practitioners.

Treating hypertension has been consistently shown to reduce the risk of cardiovascular disease and stroke, which are major health targets in New Zealand.

1 Resistant high blood pressure is defined as having a systolic blood pressure greater or equal to 160mmHg despite taking at least three blood pressure lowering medications. Normal blood pressure is less than 120mmHg (systolic) and less than 80mmHg (diastolic).

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Royal College honours top Kiwi paediatricianFormer HRC Board member, Distinguished Professor Jane Harding from the University of Auckland, is to be awarded the Howard Williams Medal for 2014 at the Royal College of Physicians Congress in Auckland next May.

Professor Jane Harding served on the HRC Board between 2001 and 2007.

The college’s Paediatrics and Child Health Division awards the medal each year to a person who has made an outstanding contribution to Paediatrics and Child Health in Australia and/or New Zealand.

This may be in the areas of research, education, teaching, administration, or in the development of special services or practice. The

announcement was made by the President of the Paediatrics and Child Health Division, Associate Professor Susan Maloney.

Professor Harding’s research activities include clinical as well as basic physiological studies. Her main interests concern the interaction of nutrients and growth factors in the regulation of growth before and after birth, and the long-term consequences of treatments given around the time of birth.

Most recently, she was the lead scientist in a part HRC-funded study (published in The Lancet in September) that developed a cheap and easy-to-administer dextrose gel to treat low blood sugar (hypoglycaemia) in newborns (read more about this study on page 11). In June this year, Professor Harding was awarded $1,197,339 in the HRC’s annual funding round to test the dextrose gel treatment in a randomised trial.

Professor Harding obtained her medical degree at the University of Auckland, and trained in fetal physiology on a Rhodes Scholarship, completing her Doctor of Philosophy at the University of Oxford. After specialist training as a paediatrician in New Zealand, she completed her FRACP in neonatology.

Her postdoctoral training was as a Fogarty Fellow at the University of California in San Francisco.

Professor Harding was appointed to the Medical and Health Sciences Faculty of the University of Auckland in 1989 and was appointed Professor of Neonatology in 1997. She is currently Deputy Vice-Chancellor (Research) for the University of Auckland and is a member of the LiFePATH research group of the university’s Liggins Institute.

News article courtesy of the University of Auckland.

2013 New Zealand Research Honours awardsThe HRC would like to congratulate all the health/science-related winners at this year’s Royal Society of New Zealand Research Honours event.

Rutherford Medal – Distinguished Professor Dame Anne Salmond, FRSNZ, from the University of Auckland in the field of anthropology.

Thomson Medal – Dr Peter Lee, Chief Executive of Auckland UniServices Limited in the field of commercialisation.

Callaghan Medal – Dr Siouxsie Wiles, from the University of Auckland, in the field of microbiology/science communication.

MacDiarmid Medal – Professor Neil Broom, from the University of Auckland, in the field of health/bioengineering.

A full list of the 2013 Research Honours medal winners can be found at www.royalsociety.org.nz.

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Virus particles set to help fight cancerBy Mark Wright

Virus-like particles (VLPs), based on the empty virus shell of rabbit calicivirus, have now been developed by University of Otago researchers to the point where they could be trialled to deliver anti-cancer vaccines and treatments in people.

Associate Professor Sarah Young

Associate Professor Sarah Young, who was awarded a HRC Sir Charles Hercus Health Research Fellowship in 2008, says the VLP looks like a virus to the body’s immune system but it can’t replicate because it doesn’t have any genetic material inside it.

“We manipulate that shell of the virus and put on bits of the tumour and other immune-activating signals that will then be able to activate the immune system. The idea is to trick your immune system into thinking that its own tumour is like the virus.”

Dr Young says the work has involved close collaboration with virologist Professor Vernon Ward, who makes the VLP, and immunologist Professor Margaret Baird, who is an expert in how the immune system is activated.

“The great thing about this calicivirus is that it acts differently to other VLPs; it enhances the killing arm of the immune response. It induces cytotoxic immune cells that specifically target and kill tumour cells.

“Other VLPs that are used in other

vaccines, like the hepatitis B vaccine or the cervical cancer vaccine, target another arm of the immune response, which is to make lots of antibodies.”

The calicivirus-based VLP gets picked up by the dendritic cells. These cells then present it to the body’s killer T cells, which then attack the tumour.

Dr Young says one of the key features is the way they also form a memory response, just as you would see with the likes of a hepatitis vaccination.

“The whole idea with vaccination is that you’ve got these memory cells that will hang around your body for a very long time. If you were ever infected by hepatitis they would kill off those virally infected cells, before it did any damage to your body.”

Working on VLPs has been a long-term project for Dr Young. Her four-year $500,000 Hercus Fellowship allowed her to focus on putting certain immune enhancers on a VLP to activate particular types of cells within the immune system.

“A second paper we’re going to publish shows that you can put this enhancer molecule on the surface of VLP and inject it intravenously. It produces a strong anti-tumour response – much more than if you don’t have it.”

Dr Young says when it comes to fighting cancer they use the term vaccine more loosely. Instead of just being a prophylactic, given to prevent disease, they also use the term to mean a therapy.

“The majority of the patients we want to treat would use it as a therapy. Once the patient has the disease we use the

VLP to treat that patient and produce their body’s own immune response to that existing tumour.

“At the moment we are looking at how our VLP would fit in with the current gold standard therapy. Patients would come in and have a surgical resection or some chemotherapy: how would the use of a VLP work alongside that?”

In many ways the VLP works like chemotherapy in that it kills off tumour cells. However, the big advantage it has is that it shouldn’t have any side effects.

“Chemotherapy is often a blunt tool. It blasts anything that is growing. This is a very specific tool only targeting specific cells and providing that memory response.”

Dr Young says they are now at the stage where they can produce clinical grade VLPs that would be adaptable to different tumour models (e.g. melanoma and lung cancer).

“It works well in all of the settings we’ve tested it in so far. It could potentially be a universal treatment, which is really exciting.”

Dr Young says they are also looking at cellular therapy. This is where they grow T cells in the lab, put them back into the affected animal and then add the VLP later to boost the immune response of those T cells.

“You can do many different manipulations with this vaccine.”

Information: Associate Professor Sarah YoungUniversity of Otago, Dunedin✆ +64 3 470 3457 [email protected]

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Study identifies significant gaps in Māori maternal health knowledgeBy Suzy Botica

A study released last month has identified four priority areas where more research is needed to better support Māori mothers and their babies.

The Hapū Ora: Wellbeing in the Early Stages of Life study1 looked at factors affecting Māori health and wellbeing in the early stages of life (hapū ora), covering the fetal/gestational and neonatal periods.

Two of the study’s authors, Massey University’s Associate Professor Helen Moewaka Barnes and Dr Angela Moewaka Barnes (both Ngā Puhi), say the research team wanted to look beyond individual behaviour and biology.

“A strongly individual focus can fail to take into account wider societal issues and causes of inequities. We’ve focused on identifying the underlying environmental influences that are shaping the lives and experiences of Māori and influencing maternal and infant wellbeing,” says Dr Helen Moewaka Barnes.

Helen and Angela worked with

co-authors Associate Professor Joanne Baxter (University of Otago, Dunedin), Dr Sue Crengle (the University of Auckland), Dr Leonie Pihama (Māori Indigenous Analysis Ltd), Dr Mihi Ratima (Taumata Associates) and Ms Bridget Robson (Wellington School of Medicine and Health Sciences).

Each took responsibility for writing up specific areas, broadly covering: contextual information; Māori concepts related to pregnancy and birth; impacts and influences on babies in utero and in the early days, including epigenetics research; stress; maternal mental health and; antenatal

At the launch of the Hapū Ora: Wellbeing in the Early Stages of Life study (from left): Kaumatua Pio Jacobs, Dr Angela Moewaka Barnes, Ms Paula Searle, Associate Professor Joanne Baxter, Associate Professor Helen Moewaka Barnes and Dr Mihi Ratima. Absent: Dr Sue Crengle, Dr Leonie Pihama and Ms Bridget Robson.

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care, labour and delivery care. These areas were then worked on collectively to integrate the report.

The study, which was funded by the HRC and the Ministry of Health, based its findings on an extensive literature review and discussions with more than 50 Māori stakeholders from throughout New Zealand. It identified gaps in knowledge at all levels of influence: national and state (macro); community (mezzo); mothers and babies (micro); and health services (exosystems).

The mental health of Māori women during pregnancy and after birth emerged as an area of particular concern. The literature review revealed high levels of mental health needs among Māori women, especially young women. There were also considerable gaps in knowledge. The authors found no research in New Zealand that directly examines discrimination as a contributor to maternal stress. This is despite international research that has found links between racism and pregnancy-related outcomes.

“There is a dearth of epidemiological research on stress and the mental health of Māori women during and post pregnancy. We found only one published research paper2 measuring postnatal depression in Māori,” says Dr Angela Moewaka Barnes.

Using the knowledge gaps and needs identified in their review and stakeholder interviews, the study’s authors developed four overarching priority areas for hapū ora. They are:

1. Ensure high quality data as a foundation for research, monitoring and evaluation Data is particularly needed on Māori birth outcomes, and maternal mental and physical health.

2. Address societal conditions such as poverty and deprivation, and meet the needs of vulnerable populations (e.g., people living

in poverty, teen parents, solo mothers) The review suggests that societal norms, systems and practices can negatively position pregnant women, new mothers and whanāu through stigma, discrimination and marginalisation.

3. Support mother, baby and whanāu through services and social support, and by better understanding stress and maternal health issues The review found that maternal health, wellbeing and behaviours can have considerable effects on babies in utero and in the early days after birth, with implications throughout their lives. Maternal mental health, diabetes, nutrition and substance use were highlighted as key areas to focus on.

4. Improve services for maternal and newborn care, including maternal mental health care Māori women experience inequalities in access to care and report lower levels of satisfaction than other women. “There could be a lot more consistency of care. We need maternal and newborn care providers to recognise and value Māori tikanga, world views and practices from pregnancy through to birth,” says Dr Helen Moewaka Barnes.

At the launch of the study, the Ministry of Health’s Manager of Māori Research, Paula Searle, said it was a very valuable piece of research and kaupapa3. It was also timely.

“I think this study will contribute greatly to the government’s National Science Challenge ‘A Better Start’, which will have its first requests for proposals released early next year. The findings identify several key factors in improving hapū ora. Early physical, social and cognitive development lays a critical foundation for health and wellbeing throughout our life,” says Ms Searle.

To view an electronic copy of the Hapū Ora: Wellbeing in the Early Stages of Life study, go to www.massey.ac.nz/massey/learning/departments/centres-research/shore/projects/hapu-ora.cfm.

Information: Associate Professor Helen Moewaka BarnesWhāriki Research Group Massey University, Auckland ✆ + 64 9 366 6136 [email protected]

Dr Angela Moewaka BarnesWhāriki Research Group Massey University, Auckland ✆ +64 9 366 6136 [email protected]

1 Moewaka Barnes, H., Moewaka Barnes, A., Baxter, J., Crengle, S., Pihama, L., Ratima, M., Robson, B. (2013) Hapū Ora: Wellbeing in the Early Stages of Life.

2 Webster, M., Thompson, J., Mitchell, E., Werry, J. (1994) Postnatal depression in a community cohort. Australia and New Zealand Journal of Psychiatry, 28(1), 42-49.

3 Kaupapa is a set of principles and ideas that inform behaviour and customs.

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Low blood sugar in newborns – how low is too low?By Suzy Botica

Data analysis from a major New Zealand study into the connection between low blood sugar levels (hypoglycaemia) and brain damage in newborn babies is now underway. The results are expected to help guide the care of millions of babies around the world.

Distinguished Professor Jane Harding

University of Auckland Distinguished Professor Jane Harding heads the HRC-funded study, which has involved testing some 400 2-year-old children born at Waikato Hospital at risk of low blood sugar levels. The main aim is to find out if having low blood sugar levels in the critical newborn period has an effect on how children grow and develop later on.

A low blood sugar level in newborn babies is most common in the first day or two after birth and occurs in up to 15 per cent of all newborns. Preterm, small, and big babies are at greater risk of having low blood sugar levels along with babies whose mothers are diabetic. Low blood sugar levels can sometimes cause brain damage, including visual problems and developmental delays.

Most of the children in the study were recruited from the Sugar Babies Study (see box feature on page 11), which looked at the effectiveness of a simple dextrose gel to treat low blood sugars in at-risk babies. Consequently, Professor Harding’s team knew the children’s exact blood sugar history from birth.

“By continuously monitoring the blood sugar levels of these babies, we’ve been able to show that there are a lot more babies with low blood sugar levels than we know about just by using routine blood tests,” says Professor Harding. “Now we need to find out what blood sugar levels, and for what duration and frequency, can cause brain damage.”

The study team tested the 2-year-old children for brain function, vision, cognitive and language development, memory, growth, general health, and family environment. In the process, they’ve developed a number of world-first techniques for assessing newborns and 2-year-olds.

One such technique involved teaming up with Distinguished Professor Geoff Chase from Canterbury University to find the best way of analysing and interpreting the babies’ continuous glucose monitoring data.

“The instruments that continuously monitor glucose levels are designed for diabetics. They don’t measure well at low levels, which is exactly what we’re interested in, and don’t take advantage of the other data we do have. Therefore, we had to develop new techniques to analyse

and calibrate the data for newborns. These techniques will now be used in future research studies and eventually in clinical practice,” says Professor Harding.

The area of the brain most often affected by low sugar levels is the visual cortex. Together with University of Auckland vision scientist Dr Ben Thompson, the study team have developed and validated new methods for assessing visual cortical function in very young children. Researchers from the university’s Auckland Bioengineering Institute are now working on adapting these techniques further for clinical use.

“It’s notoriously difficult to test vision in small children before they can tell you what they can see. These methods have the potential to provide the basis for a reliable and automated way of assessing vision in young children,” says Professor Harding.

The team have also developed a graded battery of tests for assessing executive function in 2-year-olds with the help of Dr Trecia Wouldes from the University of Auckland’s Department of Psychological Medicine. This includes measuring self-control, working memory, and the ability to learn rules and then to change them. These are important for predicting ability to learn and school performance, but again, are difficult to measure in 2-year-olds.

Professor Harding says preliminary findings suggest that children born at risk of low blood sugars remain vulnerable to developmental problems

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Simple gel helps prevent brain damage in newborns

In September this year, the international medical journal, The Lancet, published research from the Sugar Babies Study* showing that a cheap and easy-to-administer dextrose gel should be used to treat low blood sugars in newborns.

University of Auckland study leader Professor Jane Harding says it’s the first report in babies to show that

dextrose gel massaged into the

inside of the cheek is more effective than feeding alone for treating low blood sugars.

The study enrolled at-risk babies born after 35 weeks’ gestation from Waikato Women’s Hospital in Hamilton in the first 48 hours after birth. Those babies who developed low blood sugars were randomly assigned to the dextrose gel or to a placebo gel.

Treatment with dextrose gel almost halved the likelihood of treatment failure compared with the placebo, with no adverse effects. Babies given the gel were also less likely to be admitted to intensive care for low blood sugars, to receive additional

formula feeds, and to be formula fed at two weeks of age.

“Because this treatment is inexpensive and simple to administer, it should be considered for first-line management of late preterm and term hypoglycaemic babies in the first 48 hours after birth,” says Professor Harding.

*Funding for the Sugar Babies Study came from the Waikato Medical Research Foundation, the Auckland Medical Research Foundation, the Maurice and Phyllis Paykel Trust, the HRC and the Rebecca Roberts Scholarship.

News article courtesy of the University of Auckland.

at 2 years of age. She expects the first results to come through in the first half of 2014. She has also received a $2.4 million grant from the National Institutes of Health (NIH) in the US to assess the children in this study

when they turn 4 and a half years of age.

“All of these data will provide critical information about how newborn babies should be monitored and treated to prevent brain damage.”

Information: Distinguished Professor Jane HardingDeputy Vice-Chancellor (Research) The University of Auckland ✆ +64 9 373 7599 [email protected]

About HRC NewsHRC News can be viewed on the HRC website: www.hrc.govt.nzEditor: Kristine ScherpWriters: Suzy Botica Mark WrightEmail: [email protected]: PO Box 5541, Wellesley Street Auckland, 1141, New ZealandPhone: (09) 303 5200Fax: (09) 377 9988Contributions are welcome. All articles in HRC News may be reprinted, provided the writer and the source are acknowledged.ISSN 1178-9565 (Print) ISSN 1178-9557 (Online)

Secretariat staff newsWe are pleased to announce that Jaimee Dudley has been appointed as a part-time permanent Support Project Coordinator within the HRC’s Māori Health Research team. Congratulations Jaimee.

Pauline Curtis has been appointed as Policy Analyst to cover for Rebecca Luther in the Research Policy, Strategy and Evaluation team while Rebecca is on parental leave. Pauline starts in the role on Wednesday, 15 January 2014. Welcome back to the HRC Pauline.

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Curing the incurable: exploring a new protein replacement therapyBy Suzy Botica

Associate Professor Geoffrey Krissansen is one of the first recipients of the inaugural HRC Explorer Grants. Although just 6 months have passed since the grant recipients were announced, Dr Krissansen and his colleagues at the University of Auckland are excited about the prospects of their new drug delivery platform designed to combat certain incurable genetic disorders.

Associate Professor Geoffrey Krissansen

Dr Krissansen’s research team have developed a novel drug delivery platform based on a cell-penetrating peptide called Xentry, which is derived from the hepatitis B virus. Xentry can be used to deliver drugs directly to layers of cells called epithelia. These cells line organs and glands such as the skin, and respiratory and gastrointestinal tracts.

Funds from the Explorer Grant are helping the team test whether Xentry-based technologies could potentially combat two particularly cruel incurable diseases arising from single gene defects: cystic fibrosis, which affects epithelia in the lungs, and hereditary diffuse gastric cancer (HDGC), which affects epithelia in the stomach.

Both cystic fibrosis and HDGC are associated with high morbidity and lead to premature death.

The Xentry drug delivery platform, which is patented by the University of Auckland, is being employed to replace mutated proteins encoded by single genes with the normal proteins.

Dr Krissansen says that part of what makes Xentry so special is its extremely small size and unique structure.

“Large molecules don’t get across the plasma membrane of cells, which is a big problem for the pharmaceutical industry. If you can’t get inside the cell, then you can’t reach many potential drug targets,” says Dr Krissansen.

“Xentry is a tiny peptide. Its functional core is only four amino acids long, whereas most other cell-penetrating peptides are made up of between 10 and 20 amino acids. It’s also a new class of cell-penetrating peptide that can make its way across the cell membranes of virtually any cells – except, unlike all other cell-penetrating peptides, circulating blood cells. This is a distinct advantage because it means the peptide doesn’t get diluted by blood cells following intravenous delivery.”

The team’s studies in mice have shown that Xentry is taken up very strongly into epithelial cells lining the stomach, bowel, and lung.

In the case of cystic fibrosis, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupt its function, which leads to mucus build up in the lungs. Dr Krissansen and his team plan to replace the mutated CFTR protein with a normal protein by using Xentry to deliver therapeutic cargoes by an intravenous route.

“It’s believed that you would only need to restore 10 per cent of the CFTR protein’s activity back to normal to treat someone with cystic fibrosis,” says Dr Krissansen.

HDGC is a whole different scenario though, says Dr Krissansen. Whereas with cystic fibrosis you inherit a copy of the defective gene from both your mother and father, with HDGC you only need to inherit a defective E-cadherin gene from either your mother or your father. Even though you still have a ‘good’ copy of the gene, this can be deactivated to become ‘bad’ – and does so in about 80 per cent of cases.

Dr Krissansen’s research team is seeking to use the Xentry peptide to deliver a good copy of the E-cadherin gene to HDGC patients. This poses a real challenge because all of the epithelial cells in HDGC patients’ stomachs have a copy of the bad gene. This means they need to restore the epithelial cell function of as many cells as possible. The more cells they can repair, the lower the risk of cancer.

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To date, Dr Krissansen’s team have a cell line from both a cystic fibrosis patient and a HDGC patient, and are testing whether they can restore the expression of the CFTR and

E-cadherin genes in these cells. Once they’ve finished the cellular studies, they plan to move onto animal studies, hopefully towards the middle of 2014.

“We know Xentry can deliver large

cargoes into the cell. We’re now trying to improve its release from the cell’s endosomes into the cytoplasm.”

Dr Krissansen says they are trying to see how far they can push the technology.

“It’s still only early days, but I personally believe cell-penetrating peptide technology will eventually transform medical practice.”

Information: Associate Professor Geoffrey KrissansenDepartment of Molecular Medicine and Pathology, the University of Auckland ✆ +64 9 373 7599 ext 86280 [email protected]

Master’s student Jason Michael (right) is working on the cystic fibrosis project with Dr Krissansen, while PhD student Glenn Bell (left) is working on the hereditary diffuse gastric cancer project. PhD student Kristopher Montrose and technician Yi Yang (not pictured) performed the pioneering work on the development of the Xentry peptide.

Injury researcher wins national leadership award

Professor Shanthi Ameratunga (right) with Injury Prevention Network Chair Kiri Pardoe

The HRC extends its warmest congratulatons to Professor Shanthi Ameratunga, the 2013 recipient of the Injury Prevention Network Te Manaia Leadership Award.

The Te Manaia Leadership Award recognises the outstanding commitment and contribution individuals and organisations make to the national injury prevention sector. The award is convened by the Injury Prevention Network of Aotearoa New Zealand.

“Shanthi has made an outstanding contribution to the injury prevention community, both in New Zealand and internationally, through her research and workforce development activities,” says Injury Prevention Network General Manager Justine Ropata.

“She has achieved to the highest level in her academic career and has been passionately committed to training and stimulating the work of practitioners and future leaders in the field. It is for these reasons that she is a worthy recipient of a Te Manaia Leadership Award.”

Professor Ameratunga is a leading injury researcher who has achieved international acclaim. Her current research work focuses

on road traffic injuries, child and youth injury, disability and high-quality equitable trauma care and rehabilitation outcomes. She is first named investigator on two current HRC-funded projects, one looking at the determinants of life-threatening injuries among young and middle-aged adults, and the other a randomised controlled trial to investigate the effectiveness of an innovative mobile phone intervention to reduce hazardous drinking in at-risk groups.

Professor Ameratunga is currently professor of epidemiology at the University of Auckland’s School of Population Health.

In New Zealand unintentional and intentional injury is the leading cause of death for people between the ages of 1 to 34 years, and a major cause of hospitalisation.

News article courtesy of the Injury Prevention Network of Aotearoa New Zealand.

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Licence policy drives researchBy Mark Wright

If you are looking for a textbook example of research being used to shape policy then it is hard to go past the HRC-funded New Zealand Drivers Study.

Dr Rebecca Brookland (left) and Dr Dorothy BeggPhoto courtesy of the University of Otago Magazine

Run as part of a HRC-funded programme at the University of Otago, Dunedin’s Department of Preventive and Social Medicine’s Injury Prevention Research Unit, the New Zealand Drivers Study can be traced back to a pilot study in 2001. That eventually led to the 2005 launch of the full study with funding from the HRC, the Accident Compensation Corporation, and the Road Safety Trust.

Since that time it has helped provide evidence and generate debate about young drivers and the country’s licensing system. But for principal investigator Dr Dorothy Begg one of the most important things has been the way the research has fed into the development of policy.

“The actual purpose of the study was to provide evidence to influence young driver policy in New Zealand. That was what we set out to do because we could see there was a big gap there,” she explains.

Dr Begg says they originally had the funding for four years. However, a longer timeframe was needed to make the project work, especially when the recruitment phase required two years to recruit a comprehensive sample of 4000 newly licensed drivers from throughout New Zealand.

One of the first things they looked at was the licensing age and attitudes to raising it. Although they expected their cohort to be against the idea, more than half were actually in favour of the age being raised.

“The main reason they were getting their licence wasn’t for what you might call essential travel. It was mainly so they could go where they wanted and have freedom to do what they wanted to do. Independence.”

That paper helped provide evidence to go to the Parliamentary Select Committee when they met to discuss raising the driver licensing age, which they went on to do.

After the first four years of funding,

the study became part of a wider HRC-funded Injury Prevention Research Unit programme. By that stage the New Zealand Drivers Study had gone on to look at those drivers who hadn’t actually progressed on to get their restricted licence.

“A lot had just got ‘stuck’ on their learner licence. They hadn’t gone on to get their restricted licence and we weren’t sure why. We didn’t know whether they were doing a lot of unsupervised driving and just ignoring the learner licence conditions, or whether they weren’t driving at all,” says Dr Begg.

“From the follow-up interviews of those that hadn’t got their restricted licence we found that most of them weren’t driving very much at all – so they weren’t just ignoring the licensing law. That was a little surprising.”

The study also included interviews with 1200 parents of restricted drivers.

Dr Rebecca Brookland, who undertook that part of the study for her PhD, says parents were keen to have the opportunity to talk about the issues they faced.

“They felt challenged by finding that balance between giving their adolescents independence and their concerns about the crash risk and safety issues of them driving unsupervised.”

It helped Dr Brookland identify the key things that parents were doing that would influence their teen’s risk of having a crash or regularly breaching the conditions of their graduated driver licence. Those key things included parents having a crash themselves; having less rules around their adolescent’s driving; and their

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adolescent having easy access to a vehicle.

Findings from the parent study have contributed to the development of the New Zealand Transport Agency’s current ‘Safe Teen Driver’ campaign, which encourages parents to stay actively involved in their teen’s driving during their restricted licence period. Study findings have also been used by the New Zealand Transport Agency in the development of their ‘Safe Teen Vehicle’ resources.

“The restricted licence stage is still a period of learning for a young driver,” says Dr Brookland. “Crash risk is highest in the first six months of getting your restricted licence.”

Current moves to extend the period of learner licensing from six months to a year has the support of Dr Begg and her team.

“Our research would suggest that it is a good idea. Dr Pauline Gulliver had a paper published looking at driver

training and supervised driving at the learner licence stage.

“She found that time was a key factor. Learner drivers who spent longer on their learner licence had a lower crash risk when driving on their restricted licence, so we would advocate for an extended learner licence period.”

Dr Dorothy BeggUniversity of Otago, Dunedin✆ 021 1222312 [email protected]

‘The eyes have it’ in top health research Career Development Awards Three of New Zealand’s talented, up-and-coming eye researchers have each received up to $500,000 from the HRC to develop exciting new therapies for debilitating eye conditions such as cataracts and diseases of the cornea.

The trio and 11 other researchers have collectively been awarded more than $4.3 million through the HRC’s 2014 Career Development Awards programme. The HRC has also awarded a further 19 Career Development Awards in the area of Māori health (worth a total of $1.5 million) and 10 Career Development Awards for Pacific health research (worth a total of $1.09 million).

Eye surgeon and clinician Associate Professor Dipika Patel from the University of Auckland will use her HRC Clinical Practitioner Research Fellowship to further develop a new scaffold that could become a substitute for human corneal tissue. Ultimately, the scaffold would replace human donor corneas in transplant operations.

Donor corneal tissue is a limited resource in most countries. The current waiting time for cornea transplantation in New Zealand is more than a year. In many other countries, donor corneal tissue isn’t available.

“The development of a suitable tissue substitute would have a dramatic effect on reducing waiting times for surgical treatment and may enable treatment of corneal diseases that are not currently suitable for transplantation,” says Dr Patel.

If successful, she says this work will open up a wide range of avenues in the field of tissue engineering and reconstructive surgery.

Dr Angus Grey from the University of Auckland has received a Sir Charles Hercus Health Research Fellowship to tackle cataracts, the world’s most preventable form of blindness. Dr Grey will use his expertise in imaging mass spectrometry to discover what role small molecules and metabolites (substances produced during metabolism) play in the development of cataracts.

Each year some 16,000 cataract surgeries are performed in New Zealand.

Dr Grey says the research will provide

the information needed to develop novel anti-cataract therapies that use nutritional supplements to delay the progression of the cataract on the eye’s lens.

University of Auckland eye specialist Dr Ilva Rupenthal plans to use her Sir Charles Hercus Health Research Fellowship to develop biodegradable eye implants that can slowly release medication for eye diseases over up to six months. Non-invasive laser light passed through the cornea will activate the implants to provide top-up doses of medication.

“These awards are a fantastic opportunity to help some of New Zealand’s best and brightest become world-class leaders in their fields, and to translate cutting-edge research from bench to bedside,” says HRC Chief Executive Dr Robin Olds.

Check out www.hrc.govt.nz/funding-opportunities/recipients for details on all of the Career Development Award recipients, including those who have received an award in the areas of Māori and Pacific health.



Key to brain’s role in fertility identifiedBy Mark Wright

A key to understanding the brain’s role in triggering fertility has been identified through HRC-funded research at the University of Otago, Dunedin’s Centre for Neuroendocrinology, and published in the prominent international journal Nature Communications.

Professor Allan Herbison

Led by neuroscientist Professor Allan Herbison, the research has provided clear proof of the critical part played by kisspeptin, a small signalling protein that acts on the gonadotropin-releasing hormone (GnRH) neurons in the brain. The landmark discovery opens the door to new fertility treatments and new forms of contraception.

Although it was already known that kisspeptin is important in fertility, researchers’ understanding of how and where it worked was still unclear.

Professor Herbison says kisspeptin signalling was thought to occur in the brain as well as in the pituitary gland, the ovaries, the testes, and the placenta.

“What we didn’t know was what the relative importance was. Is the kisspeptin signalling in the ovaries really the important thing, or is it the kisspeptin in the brain that’s critical?”

They set up a range of experiments using strains of genetically manipulated mice in which the kisspeptin receptor Gpr54 had been removed from the small population of about 1000 GnRH neurons in the brain. As a result those mice do not go through puberty and were left completely infertile.

“That tells us that the kisspeptin signalling for GnRH cells is absolutely critical for fertility. But the clincher experiment is where you take a mouse where kisspeptin signalling has been taken out of every zone on the body, and put the correct functioning kisspeptin receptor back into just the GnRH neurons.

“Now the only place where kisspeptin can act is on the GnRH neurons. Amazingly, those mice go through puberty and become fertile,” he says.

Professor Herbison says this one small population of cells in the brain tell the pituitary what to do, and the pituitary tells the ovaries or the testes what to do.

“It’s quite a black and white result. We can now say that kisspeptin signalling at the GnRH neuron is the key for fertility.”

He says kisspeptin has been evolutionarily conserved for reproduction for billions of years.

“You can go right back to invertebrates and find kisspeptin is a key molecule that is required for fertility. When you come across something that evolution hasn’t changed much you know you are onto something that is pretty important.”

Professor Herbison says the focus is now switching to how to use kisspeptin more effectively in fertility treatment, even though only a small percentage of people are infertile because of issues with kisspeptin signalling in the brain.

“These studies have shown us that kisspeptin signalling is very important and can override other causes of infertility because it is such a powerful activator of the whole system.”

They are already planning work with clinical partners on making kisspeptin part of IVF treatment cycles.

Professor Herbison says there is also scope to develop a kisspeptin antagonist. This could have a role in developing new forms of contraception and may also have relevance to diseases such as prostate cancer in which testosterone is a key driver.

Professor Allan HerbisonUniversity of Otago, Dunedin✆ +64 3 479 [email protected]

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