Newsletter October 1997


The past three months have been a notable period for AuSPEN. In August, AuSPEN participated in the launch of the Report of the Ministerial Working Party for Home Enteral Nutrition in Victoria. This report accepted the recommendation for 'best practice' as defined by the AuSPEN Clinical Practice Guidelines for Home Enteral Nutrition in Australia. At the launch of this report the Hon Robet Knowles, Victorian Minister for Health, committed $2 million per year to support Home Enteral Nutrition Therapy in Victoria. We hope that his initiative will be examined by other States to improve the accessabliity and quality of Home Enteral Nutrition provision throughout Australia.

In October representatives from AuSPEN Membership and others with an active interest in nutrition met to discuss the role of AuSPEN in the future and develop a strategic plan for the next 5 to 10 years. The meeting was very successful and has provided a major step towards making AuSPEN a more relevant and active Society. A Subcommittee of the Strategic Planning Meeting will continue to meet to follow through with the recommendations of the meeting. We would like to invite any Members with ideas or comments to help shape the Society into a Society you believe is relevant and provides for your needs.

The Council of AuSPEN has worked hard to improve our relationships with other international societies for parenteral and enteral nutrition. There has been an international move to bring these societies together to cooperate and to improve education and research, particularly in developing countries. AuSPEN continues to plan an important role in these discussions and innovations.

Once again a Parenteral Multivitamin shortage in MVI-12 has affected many hospitals. A statement on this shortage is included in this Newsletter. Updates will appear on the AuSPEN Internet 'homepage' as developments occur.

I look forward to meeting up with many of you in Perth.

Dr Julie Bines President of AuSPEN


Dr Julie Bines, President of AuSPEN, Dept. of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne. Ph +61-3-9345-5060. Fax +61-3-9345-6240


Dr Margaret Allman, Honorary Secretary of AuSPEN, Human Nutrition Unit, Biochemistry Dept.,The University of Sydney, Sydney 2006. Ph +61-2-9351-3758 Fax +61-2-9351-6022




A serious worldwide shortage of IV multivitamins involving MVI Paediatric and MVI-12 has developed. In Australia it appears that we will experience shortages of the multivitamins over the next few months. While these shortages were initially believed to be short term, it is now feared that the problem will be more long term. In the USA there have been serious complications, including fatality, as a result of this shortage of IV multivitamins. We have suggested the following recommendations for older children and adults with regard to this IV multivitamin shortage.

(1) Monitoring for early signs of vitamin deficiency during this shortage is essential.

(2) Use oral vitamin preparations wherever possible. Patients who have severe gastrointestinal malabsorptionmay may still require parenteral vitamins. The importance of compliance to oral vitamins may need to be stressed to patients who have been unused to taking these preparations orally.

(3) Remember Thiamine

Thiamine deficiency can occur when long term PN patients do not receive multivitamins for a few weeks. This can result in death due to cardiac failure. An IV preparation of thiamine is available.

(4) Folate deficiency

Long term PN patients who have not received folate for 4 to 5 weeks may develop megaloblastic anaemia. An injectable form of folate is available.

(5) Conserve MVI-12 by reducing daily dose OR administering three times a week.

(6) Do not use MVI-Paediatric for adult patients. MVI-Paediatric is also potentially in short supply. MVI-Paediatric is the only multivitamin preparation suitable for paediatric patients in Australia, therefore the supply should be carefully protected.

(7) If a multivitamin preparation is needed and not available alternatives include :

(i) An alternative IV multivitamin preparation : Soluvit (Pharmacia & Upjohn) is available via the Special Access Scheme and administration details are available on enquiry.

(ii) Individual vitamin preparations can be given daily. Suggested doses for adults include :

Thiamine : 50 mg IV three times a week

Folate : 0.4 to 1.0 mg IV daily

Ascorbic Acid : 100 mg IV daily

Cyanococabalamin : 100 ug IM or SQ monthly

Pyridoxine : 5 - 10 mg IV daily

Any further information is available by contacting Dr Julie BInes, Dept of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Victoria.

Ph 03-9345-5060 or Fax 03-9346-6240


AuSPEN Homepage :\~hartley\home.htm



Date : Thursday 23rd October 1997

Venue : Esplanade Hotel, Fremantle

14:00 Nutritional Support - Difficulties with Access to the Enteral Route : Gary Zaloga

14:30 Difficulties in Feeding Paediatric Patients : Stan Zlotkin

15:00 Pro-Kinetic Agents. Are We Moving On ? : Ian Jenkins

16:00 Particulates, ARDS and Multiorgan Failure : Michael Barnett

16:30 Feeding the Intestine During Critical Illness : Peter Furst


The first Newsletter for 1998 will be published in January and thereafter in April, July and October. If contributors could get items to the Editor by the middle of the third week of the month preceeding that will assist greatly with the planning of the issue. If copy is not ready at that time but will be by the end of that month please let me know so that I can reserve the space.

Contributions on any relevant subject are always very welcome. If you have an idea for an article but are not too sure about its relevance do not hesitate to give the Editor a call or email to discuss and develop the idea first.


This issue of the Newsletter has received significant sponsorship towards production costs from BAXTER CLINICAL NUTRITION DIVISION.


Kevin Williams

From the following statements (currently before the auditor) it can be seen that the Society's financial position remains sound showing healthy reserves, with income exceeding expenses by $1584 for the 1996 calender year. Membership numbers remain static at around 200.

Whilst the bottom line appears healthy, in reality the cost of running the society has increased markedly over the last two to three years. The Society has decided to produce a quality newsletter for members at a cost of approx. $1500 per issue and the annual subscription for the Nutrition Journal (now issued monthly) rose to $11,000 per year. (Note that there was no journal purchased in 1996 whilst council sought members views on whether to continue the subscription and which journal was deemed most appropriate).

The Society thanks the many companies who assist with sponsorship of our Conferences and Newsletters, without which our financial state would be greatly diminished. Whilst the Society trys to keep membership fee increases to a minimum, some increase may be necessary to cover the expansion of our services. From the recent planning day, it is hoped that the Society can develop further strategies for revenue generation and Council would welcome your ideas is this area.

In summary, I would like to thank those Members whether it be as a Council Member, contributor to the newsletter or member of a Conference Organising Committee or in other capacities for all the voluntary hours of service provided to the Society, but which never appears on the balance sheet.

Thank you all for your support,

Kevin Williams




INCOME 1/1/96 - 1/1/95 31/12/96 - 31/12/95
Conference '93 700.00 100.00
Conference '95 9,483.89 0.00
Interest 1,662.81 2,174.22
Subscriptions 12,830.00 15,300.00
TOTAL INCOME 24,676.70 17,574.22

EXPENSES 1/1/96 - 1/1/95 31/12/96 - 31/12/95
Accomodation 0.00 1,325.00
Awards 300.00 0.00
Conference '96 5,117.39 0.00
Conference '97 3,500.00 0.00
Council Meeting
Conferlink 779.30 789.28
Qantas Club fee 450.00 0.00
Room Hire 691.30 0.00
Travel 6008.00 2,043.00
Total Council Meeting 7,928.60 2,832.28
Fees & Charges:
Auditing Fees 0.00 400.00
Bank Charges 754.01 288.82
Total Fees & Charges 754.01 688.82
Freight 74.00 0.00
Gifts 50.00 0.00
Legal Expenses 551.47 558.50
Newsletter 1,460.20 0.00
Nutrition Jrnl. 0.00 10,103.47
Posting 875.72 598.80
Printing 84.40 0.00
S.A. Stamp Duty 0.00 9.80
Stationery 443.10 288.20
Telephone 0.00 83.85
Travel :
Travel Grant 1,953.00 1000.00
Travel - Other 0.00 1,057.90
Total Travel 1,953.00 2,057.90
TOTAL EXPENSES 23,091.89 18,546.62
TOTAL INCOME / EXPENSE 1,584.81 -972.40

Cash & Bank Accounts
Current New 26,212.83
Term Deposit 3 11,688.34
Term Deposit 4 5,776.59
Total Cash & Bank Accounts 43,677.76
TOTAL ASSETS 43,677.76
Liabilities 0.00
Equity 43,677.76


This Association was formed in 1996 by parents and paediatric professionals with the aim of providing family support, an ongoing educational facility along with support of the research for families who have a child affected by disordered gastro-intestinal motility. This would include Hirschsprung's Disease, ano-rectal malformations, pseudo-obstruction, intestinal nueronal dysplasia short gut syndrome and those that are TPN dependent. The group holds regular meetings, produces frequent newsletters, has a network of family contacts and provides 'inhospital' visits for newly diagnosed children. A resource library is now available. Two successful and informative seminars have been held to date for parents and teachers to assist in the understanding and management od bowel disorders.

Plans for this year include :

Seminar for parents, 30th November, with guest speaker Professor John Hutson, Royal Children's Hospital, Melbourne.

Some less formal family meetings along with expansion of an educational programme for chronically ill children, which has been running successfully in Canberra now for twelve years.

The Association is now a Registered Charity and has the full support of the Paediatric Hospitals in Australia who have been most helpful during our first year.

The Association is growing steadily and would welcome any contributions from professionals and parents for our newsletters.

Contact : Eunice Gribbin, Secretary, A.P.S.A., PO Box Oakdale NSW 2570.

Ph/Fax 046-596-186


Leptin, a 16 kDa peptide product of the ob gene, acts peripherally and centrally to reduce food intake and increase body energy expenditure. A deficiency of leptin is directly linked to severe obesity. Higher levels of leptin reported in obese rodents and humans presumeably act as a negative feedback 'signal' to centres controlling energy homeostasis. High-affinity leptin-binding receptors (OB-R) have been detected in the hypothalamus. Variants of OB-R are also reported in liver and kidney, however, their function is not precisely known. The ob/ob mice develop insulin resistance in the absence of leptin suggesting that leptin may be involved in obesity-associated insulin resistance and development of non-inulin dependent diabetes mellitus.

Ravussin, E, et al, Nature Med., v3, p238, (1997)

Ahima, R S, et al, Nature, v382, p250, (1996)

Cohen, B, et al, Science, v274, p1185, (1996)

Source : Calbiochem Biologics, v23, #1, May 1997

Contact : Calbiochem-Novabiochem Pty Ltd, PO Box 140, Alexandria, NSW 2015.


The Editor has been forwarded brochures etc. on the following three meetings. Photocopies can be supplied on request.

November 13th - 16th. 2nd Australian Cystic Fibrosis Conference : The Cost of Caring, will be held the Burswood Convention Centre, Burswood, Perth, WA. Chairman : Prof Louis Landau, Executive Dean, Faculty of Medicine and Dentistry, The University of Western Australia. Main Topics : Treatment of Primary Mechanisms Genetics Respiratory Gastrointestinal and Liver Lung Transplantation Models of Cystic Fibrosis Quality and Cost Effectivenes of Care The Consumer's Perspective Who Cares for the Carers.

Contact : Australian Cystic Fibrosis Association, PO Box 254, NORTH RYDE 2113.

Ph +61-2-9878-5250 Fax +61-2-9878-5058

January 19th - 21st, 1998. 22nd Clinical Congress of ASPEN, will be held in Orlando, Florida, USA. The organisers have provided copies of the forms required to submit a Scientific Paper or a Nutrition Practice Poster. See April 1997 AuSPEN Newsletter for full details.

March 29th - April 1st 1998. 2nd International Conference of the Asia Pacific Clinical Nutrition Society : 'Clinical Nutrition and Public Health : Towards the Next MIllenium'; to be held at Hotel Riverside Majestic, Kuching, Sarawak. Conference Secretariat : Assoc Prof Geok Lin Khor, Department of Nutrition and Community Health, Faculty of Biomedical and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor Darul Ehsan, Malysia. Tel 603-9486101 Fax 603-9426957


(Conference Chairperson : Prof Mark Wahlqvist, Dept of Medicine, Monash Medical Centre, 246 Clayton Road, Melbourne, VIC 3168)


November 1st - 3rd : Annual Paediatric Nutrition Workshop: 'Nutrition during Adolescence' at Royal's Children Hospital, Brisbane, Queensland. Sponsored by Children's Nutrition Research Centre, Department of Paediatrics and Child Health, University of Queensland. Contact Charles Fleetwood, Consult Fleetwood Management Services, P.O. Box 5560, Stafford Heights, Qld 4053. Phone: 07 3264 5970, Fax: 07 3264 3520.


November 13th - 16th. 2nd Australian Cystic Fibrosis Conference : The Cost of Caring, will be held the Burswood Convention Centre, Burswood, Perth, WA. Chairman : Prof Louis Landau, Executive Dean, Faculty of Medicine and Dentistry, The University of Western Australia. Contact : Australian Cystic Fibrosis Association, PO Box 254, NORTH RYDE 2113.

Ph +61-2-9878-5250 Fax +61-2-9878-5058

November 13th - 17th. 23rd Annual Scientific Meeting of the Society of Hospital Pharmacists of Australia, Adelaide Convention Centre, South Australia. Further details from Dave Cosh, Pharmacy Dept, Repatriation General Hospital, Daw Park, SA 5041.

Ph 08-2751-799 Fax 08-3740-225


or from Hartley Management Group Pty Ltd, PO Box 20, Kent Town, SA 5071,

Ph 08-363-4399, Fax 08-3634-577,


November 30th - December 2nd. 21st Annual Scientific Meeting of the Nutrition Society of Australia, Brisbane, Queensland. Further information contact Joan Breakey, 75, Bishops Road, BEACHMERE Ph: 07-496-8207

email :

November 30th - December 3rd. 12th Brazilian Congress on Parenteral and Enteral Nutrition. Sao Paulo, Brazil. Contact Prof Dr Dan L Waitzberg, c/o Reboucas Events Coordination, Av. Reboucas, 600, CEP 05402-000, Sao Palo - 5P, Brazil.


February 6th - 8th 1998. 6th International Nurse Practitioner Conference will be held at the World Congress Centre, Melbourne. For more details contact Royal College of Nursing Australia, 1 Napier Close, DEAKIN ACT 2600. Ph 06-282-5633.

March 29th - April 1st 1998. 2nd International Conference of the Asia Pacific Clinical Nutrition Society : 'Clinical Nutrition and Public Health : Towards the Next MIllenium'; to be held at Hotel Riverside Majestic, Kuching, Sarawak. Conference Secretariat : Assoc Prof Geok Lin Khor, Department of Nutrition and Community Health, Faculty of Biomedical and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor Darul Ehsan, Malysia.

Tel 603-9486101 Fax 603-9426957


(Conference Chairperson : Prof Mark Wahlqvist, Dept of Medicine, Monash Medical Centre, 246 Clayton Road, Melbourne, VIC 3168)

April 30th - May 2nd 1998 : 8th Beijing International Symposium of Parenteral and Enteral Nutrition. Beijing International Hotel, Beijing, China. Contact : Dr Zhu-Ming Jiang, Department of Surgery, Peking Union Medical College Hospital, Geijing 100730, China. Ph 6513-4563 Fax 8610-6512-4876


September 16th - 19th 1998 : 20th ESPEN Congress on Clinical Nutrition and Metabolism will be held in Nice, France. Contact : Nice Acropolis, Development Dept., 1 Esplanade Kennedy, BP 83, 06302 Nice Cedex 4, France. Ph 33-04-9392-8300 Fax 33-04-9392-8255

October 31st - November 3rd 1998 : Growth Factors and Nutrients in Intestinal Health and Disease. International GUT Symposium, Osaka, Japan. Contact : Dr Kinya Sando, Dept of Paediatric Surgery, Osaka University Medical School, 2-2 Yamadaoka , Sui ta, Osaka, 656, Japan. Ph 81-06-8793-753 Fax 81-06-7893-759


Dr Tom Hartley

Pathology, Royal Hobart Hospital

The chemist's definition of a Free Radical is 'any species capable of independent existence and that contains one or more unpaired electron(s) in an atomic or molecular orbital'. The oxygen molecule is unique in that in it's natural state - ie. the state in atmospheric air that we breathe - it has two unpaired electrons. So it immediately qualifies to be called a free radical. Furthermore these electrons are located in what the physical chemists call 'anti-bonding' orbitals. Their existence in the orbitals actually weakens the bonds between the two oxygen atoms and in fact what is usually shown as the molecular formula of oxygen O==O should be shown as O--=O ie. one and a half bonds. Any chemical bond in a molecule involves the pairing of two electrons per bond. However, there is a rule which says that the electrons involved in a chemical bond must have opposite spins - one must be spinning clockwise and the other anti-clockwise. Fortunately for living creatures the unpaired electrons in the oxygen molecule are both spinning in the same direction - let us say clockwise. That means that if a molecule approaches and it has a spare electron also spinning clockwise then no bond can be formed between that molecule and oxygen. However, we are all familiar with how easily the feeble spark of a cigarette lighter can ignite the jet of gas - the flame is the reaction of oxygen with butane molecules. That simple spark is enough to knock the spin of one of the unpaired electrons in the oxygen molecule into an anticlockwise direction. At that point we have what is called a singlet oxygen radical that is capable of reacting with any butane molecule in the vicinity. A chain reaction follows with the heat of the flame making more singlet oxygen and now in this much more energy rich environment more free electrons are generated and two other types of oxygen free radical can be formed - the superoxide anion radical which is an oxygen molecule plus an extra electron and the peroxide radical which is plus two electrons.

Having persevered with reading this account so far you may be forgiven for wondering what relevance this is to nutrition. The catabolism of fat and carbohydrate is nothing more than controlled burning. Controlled so that the temperature in mammals remains within a tight limit of 35 +/- 5 degrees. Controlled it may be but it still involves oxygen and its free radicals. And living systems have developed sophisticated sytems to 'mop up' errant free radicals that move beyond the loci where oxidative phosphorylation and the electron transfer chain is designed to occur - in the mitochondria of the cell. So we find the enzyme superoxide dismutase which converts superoxide anion radicals to hydrogen peroxide. And catalase which converts hydrogen peroxide arising either from the superoxide dismutase reaction or from the hydrogen peroxide producing reaction between peroxide anion radicals and water. Then there are the so called antioxidant vitamins and micro-nutrients which also participate in protecting the regions beyond the mitochondria from free radical damage. If you would like to see more details on these systems then I can recommend you visit the World Wide Web site

where you will find in two electronic pages an succint account on 'Free Radicals and Oxidative Stress'. Incidentally these pages are part of the Cytokine Bulletin the index pages of which can be found at

What I hope I have achieved is an understanding that free radicals in mammals arise from that all pervading and essential ingredient for life - oxygen. In the following article by Peter Vervaart you will read about the practical aspects of the laboratory investigation and nutritional support of patients experiencing oxidative stress.


Peter Vervaart

Gastroenterology and Nutrition Section Clinical Chemistry Dept
Women's and Children's Healthcare Network
Parkville, Victoria


It is well established that free radicals or reactive oxygen species (ROS) are generated in vivo and that they can lead to cell and tissue damage; {1,2,3}. As Tom Hartley so elegantly explained in the preceeding introduction we are all faced with the paradox that oxygen, whilst essential for life, is also potentially toxic. This is also true of iron, which is also essential for life, and can, in combination with oxygen via the Fenton Cycle and/or Haber Weiss reaction produce hydroxyl radicals, superoxide anions and hydrogen peroxide 'in vivo'. As a consequence, organisms (including humans) have developed complex antioxidant defence, response and repair mechanisms to prevent the accumulation of oxidatively damaged molecules; {4,5}. It must be remembered however that all free radicals are not detrimental to the body. In fact free free radicals play important roles within the body and thus must not be percieved as always causing damage. The role of free radicals in the body include phagocytic killing via the respiratory burst {8,9}, intracellular signaling via redox sensitive transcription factors; {10}. induction of the `stress response', an adaptive response, {11,12,13}, and the induction of apoptosis or programmed cell death {6}. It is now recognised that there is an essential balance between free radicals (or oxidants) and cellular defences (antioxidants). Any perturbation in this oxidant to antioxidant balance that favours oxidation, and thus cellular damage, is termed "oxidative stress", {7}. Control of oxidative stress through monitoring of free radical processes and antioxidant supplementation is one of the newest fields of clinical medicine and is one where nutrition plays an essential role. This article will attempt to introduce readers to this new and rapidly expanding field.

Antioxidant Defence Mechansims

Defence mechanisms are found both intra- and extra-cellularly. Intracellular defence mechanisms include the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase as well as compounds such as glutathione, ubiquinol and metallothionein. Extracellular defence mechanisms include the enzyme SOD, the transition metal binding proteins ferritin, transferrin, lactoferrin, haptoglobin, caeruloplasmin, and the small molecule "sacrificial" antioxidants such as the protein thiols (glutathione and albumin), B-carotene, ubiquinol, bilirubin, urate and the antioxidant vitamins C and E. These sacrificial antioxidants are particularly interesting because they exert their effect by becoming preferentially oxidised themselves. Because they are consumed as part of their antioxidant activity there must be either a steady dietary supply or a metabolic regenerating pathway for them to have a useful biological purpose; {14,15}. It is no surprise, therefore, to find that diets rich in these small molecule antioxidants, {16,17,18}, their metabolic precursors, {19,20}, or regenerating compounds such as vitamins C and E, {17,18}, have been shown to be associated with both increased life expectancy and decreased risk of free radical-mediated disease.

Oxidative Stress

Any perturbation in the prooxidant to antioxidant balance in favour of oxidation, and thus cellular damage, is termed "oxidative stress". Conditions favouring oxidative stress include increased prooxidant activity (eg heat, trauma, infection, radiation, hyperoxia, toxins and exercise) and/or decreased antioxidant activity (eg. congenital or acquired enzyme deficiencies, nutritional deficiencies, immaturity) or both (eg sepsis, premature neonates, RDS/ARDS); {7,14,21,22}.

Cellular Responses to Oxidative Stess

At a background or low level of oxidative stress the cell undergoes normal growth and differentiation. At a medium level of oxidative stress cells have been shown to undergo a halt on cell growth and differentiation, {23}. At this level the redox sensitive transcription factors Nuclear Factor kB, (NFkB), and Activator Protein 1, (AP-1), are activated and induce stress protein synthesis via antioxidant responsive elements on stress protein genes; {10}. In much the same way factors involved in apoptotic pathways are also activated and the cell may undergo the characteristic changes associated with apoptosis; {6}. At higher levels of oxidative stress the characteristic pathological changes of free radical damage become apparent and the cell undergoes death characterised by necrosis; {24}.

Induction of "Stress Responsive Genes"

Response to ROS at the cellular level occurs through "antioxidant responsive elements", (ARE), and oxidative stress responsive genes. Following oxidative stress a signal appears to be transduced by interaction of specific DNA binding proteins with nucleotide target sequences on loci within stress inducible genes leading to transcriptional activation. AREs and oxidative stress responsive genes induce and encode proteins such as DNA repair enzymes, antioxidant enzymes, heat shock proteins, proteases, protease inhibitors, cytokines and proliferation factors. It appears likely that other antioxidant and repair genes have similar responsive elements or loci; {11,12,13}. This adaptive response also appears to be biphasic in that there is an 'early' response (1-4 hrs), which imparts relatively minor protection, and a 'late' response (12-16 hrs) which imparts major protection and involves the synthesis of proteins such as repair enzymes, but not antioxidants; {11,13}. The response also varies with the initiating stress in that some responses are global (eg induction of SOD) whereas others are specific to the initiating stress and in other cases to be tissue specific (eg induction of surfactant proteins in the lung); {11}.


Apoptosis is a morphologically distinct form of cell death involved in many physiological and pathological processes. Many agents which induce apoptosis are either oxidants or stimulators of oxidative metabolism; {6,24,25}. Conversely, many inhibitors of apoptosis have antioxidant activities or enhance cellular antioxidant defences. These include N-acetyl cysteine,{26}, antioxidant proteins, {27}, and the gene product of the oncogene bcl-228. In 1994 Buttke and Sandstrom, {6}, hypothesised the `oxygen paradox', the fact that oxygen is both essential for life but also a toxin, has been conserved through evolution for the purpose of initiating programmed cell death and apoptosis.

Pathology of Oxidative Stress

ROS can cause damage to human cells by a number of different mechanisms including direct reaction with cellular components, covalent binding to membrane components and initiation of lipid peroxidation. These have a number of different sequelae including protein carbonyl formation, DNA base oxidation, carbohydrate oxidation and lipid peroxidation. The integration of these metabolic processes involved is best summarized as follows. The initial DNA damage and direct damage to proteins has a major effect on enzyme activities within the cell. Some of the resultant metabolic changes include the depletion of ATP, glutathione (a major antioxidant) and NADH {29,30}. Furthermore, rises in intracellular free Ca2+ and Fe2+ are linked to cytoskeletal damage, membrane blebbing, membrane peroxidation and destruction, increased damage to DNA, proteins and lipids, as well as metal ion release into surrounding tissues and injury to adjacent cells; {4,5}. If the injury is very severe cell necrosis ensues, but under milder conditions, cell death due to apoptosis (programmed cell death) is possible; {6}.

Diseases of Oxidative Stress

An increasing body of evidence suggests that oxygen free radicals play a major role in the pathophysiology of various diseases and of aging. Numerous forms of inflammation, the development of genetic mutations and malignant transformations, the generation of atherosclerotic plaques in arterial walls, and the process of aging all have in common the presence and participation of oxidant free radicals. I only intend describing a few of these where nutritional intervention has been attempted with some success.

Dietary consumption of all antioxidant nutrients directly influences the circulating level of these nutrients and the activity of the antioxidant metalloenzymes. Thus, decreased intake of one or more of these antioxidants may weaken the body's defences against free radical damage and increase its susceptibility to health problems associated with such damage. It may be that sick people are under higher oxidative stress than healthy people and that antioxidant intake may not be reflected in antioxidant status because of the presence of increased oxidative stress. It is not clear whether deficiency of antioxidant nutrients predisposes to these conditions, or the deficiency develops as a result of the condition itself, because of an increased requirement for antioxidants against free radical damage; {31}.


Harman in 1957 was first to put foward that degenerative diseases associated with ageing were attributed to side effects of free radicals on cellular constituents and that antioxidants protect against the oxidative damage they cause; {32,33}. There is also evidence that as age increases the level of antioxidant enzymes such as glutathione peroxidase and intracellular antioxidants such as glutathione decreases potentiating the development of oxidative stress and damage; {34,35}. This has lead to a belief that a diet rich in antioxidants will decrease the risk of developing chronic degenerative diseases and thus increase longevity. The World Health Organisation Study Group advises that eating at least 400g/ day of fruits, vegetables and legumes may be protective against coronary heart disease and cancer.

Cardiovascular Disease

It is now well understood that free radical species are involved in the aetiology of cardiovascular disease. Solid evidence exists to support that the progression of atherosclerosis is related to the oxidation of low density lipoprotein (LDL). It has been suggested that antioxidant administration may be an important preventive factor which slows the progression and development of atheroma. The mechanism proposed is that antioxidants block the oxidative modification of LDL which may be selectively incorporated by monocytes in the arterial wall; {36}. Correlation between high plasma antioxidants levels and low risk of coronary heart disease has been shown by epidemiological studies conducted recently. There are accumulating indications that high plasma levels of a-tocopherol are associated with a lower risk of heart disease; {37}. Many studies and randomised trials are being conducted to examine the hypothesis that vitamin E and C provide protection against free radical damage. While not entirely consistent, overall the evidence already supports the use of antioxidants in coronary artery disease. There are several clinical trials currently in progress that should provide powerful evidence of the benefits patients could gain from the continual use of antioxidants in the prevention of coronary heart disease. The most interesting example is the growing evidence surrounding the so-called "French Paradox"; {38}. It has been known for quite a while that the French eat more saturated fats than people in most other western countries but suffer one- third the rate of heart disease. Current evidence suggests that a diet high in fruits, vegetables, polyunsaturated oils high in omega-3 fatty acids such as olive oil, {39}, and red wine is protective for the development of coronary artery disease. This could be due to phenoxy radicals, polyphenols and flavonoids in red wine and dietary flavonoids in onions, apples, etc., {38}, and/or increased urate generation/retention; {19}.


Over three decades ago, Randle and colleagues proposed the "glucose-fatty acid cycle" hypothesis to explain the link between insulin resistance associated with type 2 diabetes and obesity. According to this hypothesis, excessive free fatty acid (FFA) released from adipose tissue for oxidation in muscle causes the production of metabolites that inhibit glucose utilization by the muscle. Furthermore, it is now being recognized that, in addition to the previous metabolites of fatty acid oxidation implicated in the glucose-fatty acid cycle, reactive oxygen species which are by-products of fatty acid oxidation also inhibit glucose metabolism resulting in hyperglycemia, {41}. Oxidative stress has also been implicated in the development of both macro- and micro- vascular complications of diabetes. The development of these diabetic complications has usually been attributed to the nonenzymatic glycation of tissue proteins. However, it is only recently that researchers examined the possible role for free radicals in the pathogenesis of diabetes. Diabetics in general have lower levels of glutathione peroxidase and higher levels of lipid peroxides suggesting the presence of oxidative stress; {42}. This would partially explain the increased risk of cardiovascular disease in diabetic patients.

There is also agreement among researchers that glutathione, the major cellular antioxidant, plays a prominent role in the functional viability of both the exocrine and endocrine pancreas. It has already been mentioned that aged individuals have a deficiency of glutathione. It is therefore not surprising to find that, in elderly subjects with impaired glucose tolerance, acute intravenous glutathione supplementation enhanced glucose - stimulated insulin secretion; {43, 44}. Other antioxidant supplements that have been found to lower free radical concentrations and improve insulin action are vitamins C and E; {43, 45}. These antioxidant vitamins have also been found to be useful in preventing diabetic complications by working in concert with glutathione to degrade reactive oxygen species; {43}.


Oxidative stress is a key factor in this disease. There is a higher free radical production in stage II of HIV infection which may be caused by several factors including the overproduction of oxygen radicals by polymorphonuclear cells. Stores of glutathione and cysteine, one of the three amino acid components of glutathione, are deficient in HIV-infected individuals. Supplies of other antioxidants, such as vitamins A and E, also may be decreased because HIV infection interferes with nutrient absorption through the intestines, {46}.

The tat (or "transactivator") protein of the HIV promotes HIV replication within cells. It works in concert with NF-kB, whose usual function is to switch on immune cell genes as part of the normal immune response to disease, including HIV infection. Hydrogen peroxide plays a central role in activating NF-kB. The tat protein of HIV also causes a reduction in the level of intracellular superoxide dismutase. Without a sufficient supply of antioxidants, the activity of NF-kB becomes excessive and further promotes HIV replication. The rapid turnover of HIV and death of T-cells on a daily basis (over a billion T4 cells are destroyed and 50 million virus particles can be replenished every day in AIDS!) can cause increased cytokine synthesis and free radical damage of cells; {6,47,48}. In addition to increasing the rate of HIV replication, oxidative stress severely disrupts cellular activities. Oxidative stress results in damaged cell membranes, inadequate cell proliferation and cell death; {49}.

The big question in AIDS is how to restore the natural capacity of human cells to relieve oxidative stress. Nutritional education / intervention could be the answer. Studies held at the University of Miami School of Medicine determined that most HIV positive patients need 6 to 25 times the RDA of many of the vitamins/anti-oxidants to reach adequate levels in their blood; {50}. Also, a Cohort Study conducted for 11 years by researchers at UC Berkeley showed that those taking micronutrients were only 70% as likely to develop full-blown AIDS as those who did not; {51}. The consensus is that the first factor to look at is glutathione levels; {52}. Researchers have reported promising early results using N-acetylcysteine, (NAC), {53}, or the related procysteine, {54}, both of which are glutathione precursors and antioxidants in their own right. Other reports, however, are largely negative; {55}.

Down's Syndrome

Most Down's individuals have an extra chromosome 21, so they have 150% of every gene on that chromosome. Among them is the gene for superoxide dismutase (SOD) which converts superoxide anion radicals to hydrogen peroxide. This leads to a fifty percent increase in the amount of SOD in their cells and probably an increase in the concentration of hydrogen peroxide, although this has not been measured. The extra SOD is beneficial when it dismutates superoxide anion radicals to peroxide, but unless there is also additional catalase to reduce the peroxide to water, the person is still under oxidative stress from the accumulating peroxide. Therefore, Down's individuals would be expected to be under greater oxidative stress, {56}. There is also evidence of neuronal apoptosis which may explain the increased risk of early Alzeihmer's found in Down's patients; {57}. In the limited number of children that have been studied, they do indeed seem to have depleted serum levels of lipid-soluble antioxidants and vitamin C; {56}. These results are guiding special supplementation programs for these children.

Neonatal Lung Disease:

Despite recent advances in available treatments, Respiratory Distress Syndrome (RDS) and its sequelae Bronchopulmonary Dysplasia (BPD) remain important causes of morbidity and mortality in extremely premature infants. Oxidative stress is implicated because neonates are antioxidant deficient and are treated with hyperbaric O2. Study of Bronchoalveolar Lavage (BAL) has implicated oxidative stress in the development of BPD as BAL samples taken from neonates with chronic lung disease have higher levels of peroxides than samples from normal controls. There is also evidence of a failure of the oxidative stress response in these infants; {58}. Failure to increase protective endogenous antioxidant enzyme activities, during hyperoxia challenge in animal models, results in an increased susceptibility to severe oxygen-induced lung damage; {59}. Current research suggests that neonatal lung disease may be a disease of inflammmation and a failed antioxidant response. Investigation of new strategies for treating newborns with RDS involving the use of antioxidant therapies is in the early stages but is showing some promise. (Henschke and Vervaart, unpublished data).

Ischaemia-Reperfusion (IR) Injury

Ischaemia is a period when a tissue is without its blood supply. When the oxygen-rich blood supply is restored at the time of reperfusion, oxygen free radicals play an important role in inflammatory tissue damage. These events are believed to occur in cardiac and skeletal muscle, brain, intestine, liver, surgical skin flaps, etc.

Antioxidants and free radical scavengers, eg. allopurinol, SOD, {60}, catalase, desferrioxamine and N-acetylcysteine, {61}, have been shown to partially improve ischaemic tissue survival. Following IR injury in skin flaps, tissue homogenates were shown to have increased levels of lipid hydroperoxides, increased xanthine oxidase and myeloperoxidase activity and decreased levels of SOD and glutathione; {62}. This was interpreted as increased oxygen free radical activity following IR injury from both the xanthine oxidase and NADPH oxidase pathways and depletion of antioxidants in the form of glutathione and SOD.


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CRC Press have an interesting and informative page. For example if you would like to find out more about

‘Amino Acid Metabolism and Therapy in Health and Disease’ Edited by Luc A Cyanober then you could go to

where you will find four pages of information including the full Contents Pages.

Would you like to receive your copy of the AuSPEN Newsletter as an email ? If so would you prefer it as plain text format or as a hypertext document that you can view with your Internet Browser - format would be as you see it on the Homepage and you could then print it locally. Send me an email if you are interested.

Could Members who are interested in being on an email Directory let me know. All those who send me their email address will be circulated with the Membership Directory updated monthly starting as from th end of November.



The views and opinions expressed in this Newsletter are not necessarily the views and opinions of the Australian Society of Parenteral and Enteral Nutrition. Reports and articles on techniques, procedures and products is provided for the information of the Members of the Society and their inclusion does not imply any endorsements from the Australian Society of Parenteral and Enteral Nutrition. No liability can or will be accepted by AuSPEN or its agents for the third party use of information in this Newsletter.

Dr Tom Hartley, Editor, 12/10/97.