DHA status is positively related to motor development in breastfed African and Dutch infants.

OBJECTIVES: Docosahexaenoic (DHA) and arachidonic (AA) acids are important for neurodevelopment. We investigated the relation between erythrocyte (RBC) DHA and AA contents and neurological development, by assessment of General Movements (GMs), in populations with substantial differences in fish intakes. METHODS: We included 3-month-old breastfed infants of three Tanzanian tribes: Maasai (low fish, n = 5), Pare (intermediate fish, n = 32), and Sengerema (high fish, n = 60); and a Dutch population (low-intermediate, fish, n = 15). GMs were assessed by motor optimality score (MOS) and the number of observed movement patterns (OMP; an MOS sub-score). RBC-DHA and AA contents were determined by capillary gas chromatography. RESULTS: We found no between-population differences in MOS. OMP of Sengerema infants (high fish) was higher than OMP of Dutch infants (low-intermediate fish). MOS related to age. OMP related positively to infant age (P < 0.001) and RBC-DHA (P = 0.015), and was unrelated to ethnicity and RBC-AA. DISCUSSION: The positive relation between RBC-DHA and the number of observed movement patterns of 3-month old infants might reflect the connection of DHA with motor development.

Gestational age dependent changes of the fetal brain, liver and adipose tissue fatty acid compositions in a population with high fish intakes.

INTRODUCTION: There are no data on the intrauterine fatty acid (FA) compositions of brain, liver and adipose tissue of infants born to women with high fish intakes. SUBJECTS AND METHODS: We analyzed the brain (n=18), liver (n=14) and adipose tissue (n=11) FA compositions of 20 stillborn infants with different gestational ages (range 8-38 weeks) born to Tanzanian women with low linoleic acid (LA) intakes and high intakes of docosahexaenoic (DHA) and arachidonic (AA) acids from local fish. RESULTS AND DISCUSSION: With advancing gestation, brain saturated-FA (SAFA; in g/100g FA), polyunsaturated-FA (PUFA), DHA, 20:3ω6, 22:4ω6 and 22:5ω6 increased, while monounsaturated-FA (MUFA), 20:3ω9, 22:3ω9 and AA decreased. Decreasing brain AA might be caused by increasing AA-metabolism to 20:3ω6, 22:4ω6 and 22:5ω6. In the liver, SAFA, PUFA and LA increased, while MUFA decreased with gestation. The steep increase of (mostly de novo synthesized) SAFA in adipose tissue coincided with relative decreases of MUFA, PUFA, DHA, LA and AA with advancing gestation. Compared to Western infants, the currently studied African infants had higher DHA, lower AA, and a higher DHA/AA-ratio in brain and adipose tissue, while the LA content of adipose tissue was lower. CONCLUSION: The low LA and high DHA and AA intakes by the mothers of these infants might support optimal α-linolenic (ALA) vs. LA competition for Δ5D and Δ6D-activities and DHA vs. AA antagonism. Conversely, the Western diet, characterized by high LA and lower DHA and AA intakes, might disturb these evolutionary conserved mechanisms aiming at an optimal ω3/ω6-balance.

Gestational age dependent content, composition and intrauterine accretion rates of fatty acids in fetal white adipose tissue.

BACKGROUND: Little is known about the gestational age (GA) dependent content, composition and intrauterine accretion rates of fatty acids (FA) in fetal white adipose tissue (WAT). OBJECTIVE & DESIGN: To acquire this information, we collected abdominal subcutaneous WAT samples from 40 preterm and term fetuses. Their GA ranged from 22 to 43 weeks. FA were expressed as mg/g wet WAT and g/100g FA (g%). Intrauterine WAT FA accretion rates were estimated for appropriate (AGA) and large (LGA) for gestational age infants. RESULTS: From 25 to 40 weeks gestation, saturated-FA (SAFA) increased from 83 to 298 mg/g WAT and monounsaturated-FA (MUFA) from 83 to 226 mg/g WAT, while polyunsaturated-FA (PUFA) increased insignificantly from 18.0 to 23.2 mg/g WAT. As percentages of total FA, SAFA increased from 46 to 55 g%, MUFA decreased from 44 to 41 g%, and PUFA from 10.3 to 4.26 g%. Docosahexaenoic (DHA) and arachidonic acid (AA) accretion rates in WAT during the 3rd trimester for AGA infants were 88 and 193 mg/week, respectively. Contemporaneous DHA and AA accretion rates for 4500 g LGA infants were 184 and 402 mg/week, respectively. Compared to the whole 3rd trimester, increment rates during the last 5 weeks of gestation were about 2-fold higher. CONCLUSION: FA accretion rates, notably those of DHA and AA, may be important for designing nutritional regiments for preterm infants. The current WAT-DHA and WAT-AA accretion rates are considerably lower than previously reported in the literature.

Long-chain polyunsaturated fatty acids in maternal and infant nutrition.

Homo sapiens has evolved on a diet rich in alpha-linolenic acid and long chain polyunsaturated fatty acids (LCP). We have, however, gradually changed our diet from about 10,000 years ago and accelerated this change from about 100 to 200 years ago. The many dietary changes, including lower intake of omega3-fatty acids, are related to 'typically Western' diseases. After a brief introduction in essential fatty acids (EFA), LCP and their functions, this contribution discusses our present low status of notably LCPomega3 in the context of our rapidly changing diet within an evolutionary short time frame. It then focuses on the consequences in pregnancy, lactation and neonatal nutrition, as illustrated by some recent data from our group. We discuss the concept of a 'relative' EFA/LCP deficiency in the fetus as the outcome of high transplacental glucose flux. This flux may in the fetus augment de novo synthesis of fatty acids, which not only dilutes transplacentally transported EFA/LCP, but also causes competition of de novo synthesized oleic acid with linoleic acid for delta-6 desaturation. Such conditions were encountered by us in mothers with high body mass indices, diabetes mellitus and preeclampsia. The unifying factor might be compromised glucose homeostasis. In search of the milk arachidonic acid (AA) and docosahexaenoic acid (DHA) contents of our African ancestors, we investigated women in Tanzania with high intakes of freshwater fish as only animal lipid source. These women had milk AA and DHA contents that were well above present recommendations for infant formulae. Both studies stimulate rethinking of 'optimal homeostasis'. Subtle signs of dysbalanced maternal glucose homeostasis may be important and observations from current Western societies may not provide us with an adequate basis for dietary recommendations.

Neurologic condition of healthy term infants at 18 months: positive association with venous umbilical DHA status and negative association with umbilical trans-fatty acids.

Prenatal long-chain polyunsaturated fatty acids (LCPUFAs) and trans-fatty acids may affect neurodevelopment. In healthy term children, we determined relationships between relative fatty acid contents of umbilical arteries and veins and neurodevelopment at 18 mo. The study comprised a mixed group of 317 breast-fed, formula-fed, and LCPUFA formula-fed children. Study endpoints were the Hempel neurologic examination resulting in a neurologic classification and neurologic optimality score (NOS), and the Bayley Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI). Fifteen children showed minor neurologic dysfunction (MND). The umbilical vein trans, trans-18:2n-6 content was higher in children with MND than in the normal group. The NOS was significantly reduced in infants with an umbilical vein docosahexaenoic acid (DHA) content within the lowest quartile. Umbilical vein arachidonic acid (AA) was related to NOS in univariate statistics but not in multivariate analyses. The sum of trans-fatty acids and that of C18 trans-fatty acids showed a negative association with NOS in both univariate and multivariate analyses. No associations were found between AA, DHA and total trans-fatty acids with PDI or MDI. In conclusion, neonates with a relatively low DHA status and those with high trans-fatty acid levels have a less favorable neurologic condition at 18 mo.

Relationship between umbilical cord essential fatty acid content and the quality of general movements of healthy term infants at 3 months.

Prenatal essential fatty acid (EFA) status might be an important factor in the development of the central nervous system (CNS). The aim of the present study was to evaluate the relationship between the fatty acid compositions of the umbilical blood vessels at birth, used as a proxy of prenatal EFA status, and quality of general movements (GMs) at 3 mo. Umbilical artery and vein fatty acid compositions were investigated in a mixed group of breastfed infants and infants fed with formula with or without long-chain polyunsaturated fatty acid (LCPUFA) supplementation. At the age of 3 mo, video assessment of the quality of GMs was performed to evaluate neurologic condition. The quality of GMs was scored by assessing the degree of variation, complexity, and fluency. Outcomes were classified as normal-optimal, normal suboptimal, mildly abnormal, and definitely abnormal movements. Information on potential confounders, including the type of postnatal feeding, was collected prospectively. Associations between fatty acid status at birth and quality of GMs were investigated, and multinomial logistic regression analyses were carried out. None of the infants showed definitely abnormal movements. Infants with mildly abnormal GMs had a lower EFA index, lower arachidonic acid (AA) content, higher total n-9 fatty acid, and higher total monounsaturated fatty acid (MUFA) content in the umbilical artery compared with infants with normal GMs. Multivariate analyses confirmed these findings. We conclude that mildly abnormal GMs are associated with a less favorable EFA status in the umbilical artery.

High contents of both docosahexaenoic and arachidonic acids in milk of women consuming fish from lake Kitangiri (Tanzania): targets for infant formulae close to our ancient diet?

Current recommendations for arachidonic (AA) and docosahexaenoic (DHA) acids in infant formulae are based on milk of Western mothers. Validity may be questioned in view of the profound dietary changes in the past 100 years, as opposed to our slowly adapting genome. Hominin evolution occurred in the proximity of East-African freshwater lakes and rivers and early homo sapiens had higher intakes of AA and DHA from a predominantly lacustrine-based diet. In search of milk AA and DHA contents of our African ancestors, we investigated the milk of 29 lactating women living in Doromoni near lake Kitangiri (Tanzania). They consumed sunflower oil-fried local fish as only animal lipid sources, maize and local vegetables. AA and DHA contents of Doromoni milk may be close to that of early homo sapiens, because of the similarity of their life-long consumption of East-African lacustrine-based foods. Human milk fatty acid relationships from our historical worldwide database and the literature revealed that disparities between the Doromoni diet and the presumed ancient diet (i.e. higher carbohydrate and linoleic acid intakes) are unlikely to affect milk AA and DHA contents. Doromoni milk had high contents of AA (median 0.70 mol%), DHA (0.75) and eicosapentaenoic acid (EPA, 0.17), and low AA/DHA ratios (median 0.91; 0.55-2.61). This tracks down to consumption of fish with high AA and DHA contents, and AA/EPA ratios. We conclude that the milk AA, DHA and EPA contents of Doromoni women might provide us with clues to optimize infant formulae and perhaps the milk of Western women.

Lower fetal status of docosahexaenoic acid, arachidonic acid and essential fatty acids is associated with less favorable neonatal neurological condition.

Long-chain polyunsaturated fatty acids, notably arachidonic (AA) and docosahexaenoic (DHA) acids are abundant in brain and may be conditionally essential in fetal life. We investigated umbilical artery (UA) and vein (UV) fatty acid compositions and early neonatal neurological condition in 317 term infants. Neurological condition was summarized as a clinical classification and a 'neurological optimality score' (NOS). Neurologically abnormal infants (n=27) had lower UV DHA and essential fatty acid (EFA) status. NOS correlated positively with AA (UV), and EFA (UV) and DHA status (UV and UA) and negatively with 18:2omega6 and omega9 (UV), and 20:3omega9, omega7 and C18 trans fatty acids (UV and UA). UV DHA, AA, saturated fatty acids, gestational age and obstetrical optimality score explained 16.2% of the NOS variance. Early postnatal neurological condition seems negatively influenced by lower fetal DHA, AA and EFA status. C18 trans fatty acids and 18:2omega6 may exert negative effects by impairment of LCP status.

Perinatal risk factors for bronchial hyperresponsiveness and atopy after a follow-up of 20 years.

BACKGROUND: Perinatal risk factors are associated with lung function and respiratory symptoms in adult life. Whether the same holds for distinctive asthma features, such as bronchial hyperresponsiveness (BHR) and atopy, has scarcely been studied. OBJECTIVE: We sought to identify the perinatal risk factors for the development of BHR and atopy. METHODS: BHR and atopy were measured after 20 years' follow-up in 597 of 3162 babies born from 1975 through 1978. Factors directly related to delivery of these children were studied in association with the presence of BHR and atopy. RESULTS: Twenty-five percent had BHR, and 47% had atopy. Delivery duration of longer than 12 hours was associated with the development of atopy (odds ratio [OR], 2.24; 95% CI, 1.30-3.86), and severe respiratory infection in the first year of life was associated with the development of BHR (OR, 2.69; 95% CI, 1.41-5.16). Nonatopic subjects born after induced labor and current smokers were more likely to have BHR (ORs of 2.41 [95% CI, 1.07-5.41] and 2.50 [95% CI, 1.12-5.59], respectively). Prenatal smoke exposure and childhood pet keeping decreased the risk for atopy, especially in BHR-positive subjects (ORs of 0.51 [95% CI, 0.27-0.99] and 0.46 [95% CI, 0.24-0.88], respectively). CONCLUSIONS: It has been shown that events before or during birth still have an effect on respiratory health 20 years later. We put forward that an extreme hormonal status during delivery primes the fetal immune system toward atopy development. Furthermore, a severe respiratory infection in the first year of life appears associated with BHR development, and prenatal smoke exposure might be protective for the development of atopy, yet explanatory mechanisms are lacking thus far.

The possible role of essential fatty acids in the pathophysiology of malnutrition: a review.

Biochemical evidence of essential fatty acid deficiency (EFAD) may exist in protein-energy malnutrition (PEM). EFAD is characterised by low 18:2omega6, often in combination with low 20:4omega6 and 22:6omega3, and high 18:1omega9 and 20:3omega9. Some PEM symptoms, notably skin changes, impaired resistance to infections, impaired growth rate and disturbed development may at least partly be explained by EFAD. One or more of the following factors could induce EFAD in PEM: low EFA intake, poor lipid digestion, absorption, transport, desaturation and increased EFA beta-oxidation and peroxidation. EFAD may perpetuate itself by decreasing lipid absorption and transport, and aggravate PEM by impairing nutrient absorption and dietary calorie utilisation. Micronutrient deficiencies may contribute to the impaired EFA bioavailability and metabolism. Nutritional rehabilitation strategies in PEM may consider adequate intakes of EFA and micronutrients, e.g. by promoting breastfeeding. More research is required to gain detailed insight into the role of EFAD in PEM.

Long-chain polyunsaturated fatty acids have a positive effect on the quality of general movements of healthy term infants.

BACKGROUND: Whether long-chain polyunsaturated fatty acids (LCPs) play a role in the development of the young nervous system in term infants is debated. OBJECTIVE: We investigated whether supplementation of formula with LCPs for 2 mo improves the quality of general movements (GMs) in healthy term infants at 3 mo of age. DESIGN: A prospective, double-blind, randomized controlled study was conducted with 2 groups of healthy term infants: a control-formula (CF) group (n = 131) and an LCP-supplemented-formula (LF) group (n = 119). A breastfed (BF) group (n = 147) served as a reference. Information on potential confounders was collected at enrollment. Videotapes were made of the infants' spontaneous motor behavior at 3 mo of age to assess the quality of their GMs. On the basis of quality, normal GMs were classified as normal-optimal or normal-suboptimal, and abnormal GMs were classified as mildly or definitely abnormal. Attrition at 3 mo of age was 15% and nonselective. Multivariate regression analyses with adjustment for confounders were carried out to evaluate the effect of the type of feeding. RESULTS: None of the infants had definitely abnormal GMs. Infants in the CF group had mildly abnormal GMs significantly more often than did infants in the LF and BF groups (31% compared with 19% and 20%, respectively). Infants in the BF group had normal-optimal GMs more frequently than did infants in the LF and CF groups (34% compared with 18% and 21%, respectively). Logistic regression analyses confirmed these findings. CONCLUSION: Supplementation of healthy term infants with LCPs during the first 2 mo of life reduces the occurrence of mildly abnormal GMs.

Comparison of polychlorinated biphenyl levels across studies of human neurodevelopment.

Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain, and detectable amounts are in the blood of almost every person in most populations that have been examined. Extensive evidence from animal studies shows that PCBs are neurotoxins, even at low doses. Interpretation of human data regarding low-level, early-life PCB exposure and subsequent neurodevelopment is problematic because levels of exposure were not similarly quantified across studies. We expressed the exposure levels from 10 studies of PCB and neurodevelopment in a uniform manner using a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. The median concentration of PCB 153 in the 10 studies ranged from 30 to 450 ng/g serum lipid, and the median of the 10 medians was 110 ng/g. We found that (a)) the distribution of PCB 153 exposure in most studies overlapped substantially, (b)) exposure levels in the Faroe Islands study were about 3-4-fold higher than in most other studies, and (c)) the exposure levels in the two recent U.S. studies were about one-third of those in the four earlier U.S. studies or recent Dutch, German, and northern Québec studies. Our results will facilitate a direct comparison of the findings on PCBs and neurodevelopment when they are published for all 10 studies.

Effects of prenatal PCB and dioxin background exposure on cognitive and motor abilities in Dutch children at school age.

OBJECTIVE: Our purpose was to evaluate whether effects of exposure to environmental levels of PCBs and dioxins on development in the Dutch cohort persist until school age. STUDY DESIGN: In the Dutch PCB/dioxin study, cognitive and motor abilities were assessed with the McCarthy Scales of Children's Abilities in children at school age. During infancy, half of this population was fully breast-fed for at least > or = 6 weeks and the other half formula fed. Prenatal exposure to PCBs was defined as the sum of PCB118, 138, 153, and 180 in maternal and cord plasma. In breast milk, additional measurements of 17 dioxins, 6 dioxin-like PCBs, and 20 nondioxin-like PCBs were done. RESULTS: Negative effects of prenatal PCB and dioxin exposure on cognitive and motor abilities were seen when parental and home characteristics were less optimal. These effects were not measurable in children raised in more optimal environments. CONCLUSIONS: Neurotoxic effects of prenatal PCB and dioxin exposure may persist into school age, resulting in subtle cognitive and motor developmental delays. More optimal intellectual stimulation provided by a more advantageous parental and home environment may counteract these effects of prenatal exposure to PCBs and dioxins on cognitive and motor abilities.

Trans isomeric octadecenoic acids are related inversely to arachidonic acid and DHA and positively related to mead acid in umbilical vessel wall lipids.

Long-chain PUFA play an important role in early human neurodevelopment. Significant inverse correlations were reported between values of trans isomeric and long-chain PUFA in plasma lipids of preterm infants and children aged 1-15 yr as well as in venous cord blood lipids of full-term infants. Here we report FA compositional data of cord blood vessel wall lipids in 308 healthy, full-term infants (gestational age: 39.7 +/- 1.2 wk, birth weight: 3528 +/- 429 g, mean +/- SD). The median (interquartile range) of the sum of 18-carbon trans FA was 0.22 (0.13) % w/w in umbilical artery and 0.16 (0.10) % w/w in umbilical vein lipids. Nonparametric correlation analysis showed significant inverse correlations between the sum of 18-carbon trans FA and both arachidonic acid and DHA in artery (r = -0.38, P < 0.01, and r = -0.20, P < 0.01) and vein (r = -0.36, P < 0.01, and -0.17, P < 0.01) wall lipids. In addition, the sum of 18-carbon trans FA was significantly positively correlated to Mead acid, a general indicator of EFA deficiency, in both artery (r = +0.35, P < 0.01) and vein (r = +0.31, P< 0.01) wall lipids. The present results obtained in a large group of full-term infants suggest that maternal trans FA intake is inversely associated with long-chain PUFA status of the infant at birth.

Outcome of teenage pregnancy in St. Vincent: neonatal outcome and adequacy of milk from teenage mothers

In a longitudional study, pregnancy, neonatal outcome and lactation performance of adolescent and adult primigravidae were examined and compared in 33 randomly selected women (14-25 years) in St. Vincent. The whole group of women were subdivided into three sub-groups: Group I (n=10, age 14-16 years), Group II (n=12, age 17-18 years), and Group III (n=11, age 19-25 years). Detailed data on obstetrical and neonatal (neurological) outcome were collected. After birth, information was obtained on early infant growth, maternal dietary intake and breast milk composition. Milk samples (transitional and mature milk) and maternal dietary information and neonatal anthropometric measurements were collected twice during the first month after birth through home visits. Between the 3 groups no significant differences in obstetric conditions, birthweight and early infant growth were found. The Neurological Optimality Score (NOS) was comparable for all groups, but a trend of more infants diagnosed as neurologically "suspect" infants in the younger age group shows the urgent need for more research in this field. Regarding the analysis of breastmilk samples, apart from lactose content, no major differences in the composition of macro-nutrients were found. Concerning the fatty acid composition of the milk fat, no major differences between the groups occurred, although a small number of individual fatty acids were different between the groups. Early infant growth patterns were similar in all groups. It is concluded that previously reported perinatal problems of healthy teenage primigravidae (14-16 years) were not substantiated fully in this series but neonatal outcome of infants of these mothers suggests that careful developmental follow-up of these children is indicated (AU)

Outcome of teenage pregnancy in St. Vincent: the adequacy of milk from teenage mothers in relation to neonatal growth - abstract

In a longitudinal study pregnancy, neonatal outcome and lactation performances of adolescent and adult primigravidae were examined and compared in 33 randomly selected women (14-25 years of age) in St. Vincent. The whole group of women were subdivided in three subgroups: Group I (n=10, age 14-16 years), Group II (n=12, age 17-18 years) and Group III (n=11, age 19-25 years). Detailed data on obstetrical and neonatal (neurological) outcome were collected. After birth information was obtained on early infant growth, maternal dietary intake and breast milk composition. Milk samples (transitional and mature milk) and maternal dietary information were collected twice during home visits, together with neonatal anthropometric measurements. Between the 3 groups no significant differences in obstetrical conditions, birth weight and early infant growth were found. However, in the youngest group the number of infants diagnosed as neurologically "suspect" was higher compared to the older groups. Regarding the analysis of breast milk samples, apart from lactose content, no major differences in the composition of macro-nutrients were found. Concerning the fatty acid composition of the milk fat no major differences between groups occurred, although a small number of individual fatty acids were different between the groups. It is concluded that previously reported perinatal problems of healthy teenage primigravidae (14-16 years) are not substantiated in this series (AU)

Perinatal and neonatal care at the Port-of-Spain General Hospital, Trinidad: an analysis of mortality - abstract

In this retrospective study the following information was recorded for all 1,296 infants born in 1990 and admitted to the neonatal ward, General Hospital, Port-of-Spain: date of birth, gestational age, birthweight, Apgar scores after one and five minutes, type of delivery, foetal presentation, mother's address and data concerning death. The annual perinatal mortality rate was 25.2 per 1,000 live births. The neonatal mortality rate (NMR) equaled 12.8 per 1,000 live births and the still birth rate was 15.0 per 1,000 births. The NMR for the month of August was remarkably high. During the past ten years, the NMR showed a sharp decline since 1982. From a regression analysis, birthweight (R2 = .27), Apgar score after five minutes (R2 = .26) and gestational age (R2 = .22) emerged as predictors of neonatal mortality. Birthweight-specific NMRs in infants born in a regional hospital were equal to or higher than our monthly, yearly and interhospital variations in mortality rates, although the effects of differences in the study populations cannot be completely excluded (AU)

Indicators of long chain polyunsaturated fatty acid status of exclusively breastfed infants at delivery and after 20-22 days

The fatty acid composition of plasma cholesterol esters (CE), erythrocytes (RBC) and mature milk from seven lactating women and their exclusively breastfed newborns, living on Dominica, were studied. Blood samples were taken from umbilical cord and mother at birth. A sample of breastmilk was collected on day 20-22 postpartum, together with a blood sample from the baby. At birth, cord blood plasma CE and RBC total long chain polyunsaturated fatty acid (LC-PUFA) contents were higher, and linoleic (18:2c, omega 6) and alpha-linolenic (18:3c, omega 3) acid contents lower, than in corresponding maternal compartments. Cord blood RBC LC-PUFA omega 3 content was lower and LC-PUFA omega 6 content higher than in maternal RBC. After birth, feeding with human milk led to a drop in LC-PUFA content in the plasma CE fraction, whereas RBC LC-PUFA content remained virtually constant. Current understanding of the origin and relative affinity of fatty acids incorporated in plasma CE and RBC suggests that RBC LC-PUFA content is a more reliable parameter for LC-PUFA status than plasma CE LC-PUFA content. The RBC LC-PUFA data suggest therefore that at birth the newborn has a lower LC-PUFA omega 3 status than the mother, and that this does not change during three weeks of exclusive breastfeeding (AU)