Publications by authors named "Gisela Wilcox"

15 Publications

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Dietary Management, Clinical Status and Outcome of Patients with Citrin Deficiency in the UK.

Nutrients 2020 Oct 29;12(11). Epub 2020 Oct 29.

Birmingham Women's and Children's Hospital, Birmingham B4 6NH, UK.

Background: Little is known about the optimal dietary treatment for citrin deficiency. Our aim is to describe the management of UK citrin deficiency patients.

Methods: A longitudinal retrospective review was performed. Data were collected from medical records on presenting signs and symptoms, dietary management and clinical outcome.

Results: data were collected on 32 patients from 21 families. 50% were females (16/32). Median age at diagnosis was 4 y (5 days-35 y) with 12 patients diagnosed in the neonatal period with neonatal intrahepatic cholestasis (NICCD), eight later in childhood (FTTDCD) and 12 by family screening based on index cases from five families. No patient had adult-onset type II citrullinemia. The patient age at the time of data collection was a median of 11 y (1-44 y). 91% (29/32) of patients had normal physical and neurological development, 47% (15/32) experienced recurrent unexplained abdominal pain and 9% (3/32) episodes of hypoglycaemia. Siblings had different phenotypes (5 families had > 1 affected patient). Most patients preferred high protein foods, limiting sugar-containing foods. Only 41% (13/32) were prescribed a low CHO, high protein, high fat diet (restriction varied) and two used medium chain triglyceride (MCT) supplements. No patient was prescribed drug therapy. Twenty-five per cent (8/32) of patients were underweight and 41% (13/32) had height <-1 z-scores.

Conclusions: patients presented with various phenotypes, symptoms and suboptimal growth. Symptoms and biochemical markers improved with age, but height remained low in some. More research is necessary to assess the effectiveness of dietary approaches in improving clinical outcomes and symptoms in citrin deficiency.
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http://dx.doi.org/10.3390/nu12113313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693899PMC
October 2020

Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients.

Orphanet J Rare Dis 2019 12 4;14(1):285. Epub 2019 Dec 4.

Beatrix Children's Hospital, Groningen, Division of Metabolic Diseases, University of Groningen, University Medical Center Groningen, CA33, PO box 30.001, 9700 RB, Groningen, Netherlands.

Background: Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and dietary phenylalanine and tyrosine restriction improves physical health and life expectancy in Tyrosinemia type 1 (TT1). However, neurocognitive outcome is suboptimal. This study aimed to investigate behavior problems and health-related quality of life (HR-QoL) in NTBC-dietary-treated TT1 and to relate this to phenylalanine and tyrosine concentrations.

Results: Thirty-one TT1 patients (19 males; mean age 13.9 ± 5.3 years) were included in this study. Emotional and behavioral problems, as measured by the Achenbach System of Empirically Based Assessment, were present in almost all domains. Attention and thought problems were particularly evident. HR-QoL was assessed by the TNO AZL Children's and Adults QoL questionnaires. Poorer HR-QoL as compared to reference populations was observed for the domains: independent daily functioning, cognitive functioning and school performance, social contacts, motor functioning, and vitality. Both internalizing and externalizing behavior problems were associated with low phenylalanine (and associated lower tyrosine) concentrations during the first year of life. In contrast, high tyrosine (and associated higher phenylalanine) concentrations during life and specifically the last year before testing were associated with more internalizing behavior and/or HR-QoL problems.

Conclusions: TT1 patients showed several behavior problems and a lower HR-QoL. Associations with metabolic control differed for different age periods. This suggests the need for continuous fine-tuning and monitoring of dietary treatment to keep phenylalanine and tyrosine concentrations within target ranges in NTBC-treated TT1 patients.
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http://dx.doi.org/10.1186/s13023-019-1259-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894144PMC
December 2019

International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria.

Mol Genet Metab 2019 05 26;127(1):1-11. Epub 2019 Apr 26.

Genetic Metabolic Disorders Service, University of Sydney, Children's Hospital Westmead Clinical School, Sydney, NSW, Australia. Electronic address:

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360-2000 μmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.
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http://dx.doi.org/10.1016/j.ymgme.2019.04.004DOI Listing
May 2019

Impact of pregnancy on inborn errors of metabolism.

Authors:
Gisela Wilcox

Rev Endocr Metab Disord 2018 03;19(1):13-33

School of Medical Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester, UK.

Once based mainly in paediatrics, inborn errors of metabolism (IEM), or inherited metabolic disorders (IMD) represent a growing adult medicine specialty. Individually rare these conditions have currently, a collective estimated prevalence of >1:800. Diagnosis has improved through expanded newborn screening programs, identification of potentially affected family members and greater awareness of symptomatic presentations in adolescence and in adulthood. Better survival and reduced mortality from previously lethal and debilitating conditions means greater numbers transition to adulthood. Pregnancy, once contraindicated for many, may represent a challenging but successful outcome. Successful pregnancies are now reported in a wide range of IEM. Significant challenges remain, given the biological stresses of pregnancy, parturition and the puerperium. Known diagnoses allow preventive and pre-emptive management. Unrecognized metabolic disorders especially, remain a preventable cause of maternal and neonatal mortality and morbidity. Increased awareness of these conditions amongst all clinicians is essential to expedite diagnosis and manage appropriately. This review aims to describe normal adaptations to pregnancy and discuss how various types of IEM may be affected. Relevant translational research and clinical experience will be reviewed with practical management aspects cited. Based on current literature, the impact of maternal IEM on mother and/or foetus, as well as how foetal IEM may affect the mother, will be considered. Insights gained from these rare disorders to more common conditions will be explored. Gaps in the literature, unanswered questions and steps to enhance further knowledge and systematically capture experience, such as establishment of an IEM-pregnancy registry, will be summarized.
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http://dx.doi.org/10.1007/s11154-018-9455-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208575PMC
March 2018

Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing.

Arch Dis Child 2017 11 3;102(11):1019-1029. Epub 2017 May 3.

Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester NHS Trust, Manchester Academic Health Science Centre, Manchester, UK.

Background: Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches.

Methods: We designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs.

Results: In 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses. Causal mutations were identified significantly more frequently when the biochemical phenotype suggested a specific IEM or a group of IEMs (p<0.0001), demonstrating the pivotal role of prior biochemical testing in guiding NGS analysis. The NGS panel helped to avoid further invasive, hazardous, lengthy or expensive investigations in 69% individuals (p<0.0001). Additional functional testing due to novel or unexpected findings had to be undertaken in only 3% of subjects, demonstrating that the use of NGS does not significantly increase the burden of subsequent follow-up testing. Even where a molecular diagnosis could not be achieved, NGS-based approach assisted in the management and counselling by reducing the likelihood of a high-penetrant genetic cause.

Conclusion: NGS has significant clinical utility for the diagnosis of IEMs. Biochemical testing and NGS analysis play complementary roles in the diagnosis of IEMs. Incorporating NGS into the diagnostic algorithm of IEMs can improve the accuracy of diagnosis.
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http://dx.doi.org/10.1136/archdischild-2017-312738DOI Listing
November 2017

Novel PEX11B Mutations Extend the Peroxisome Biogenesis Disorder 14B Phenotypic Spectrum and Underscore Congenital Cataract as an Early Feature.

Invest Ophthalmol Vis Sci 2017 01;58(1):594-603

Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, The University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom 3Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, United Kingdom.

Purpose: Peroxisomes perform complex metabolic and catabolic functions essential for normal growth and development. Mutations in 14 genes cause a spectrum of peroxisomal disease in humans. Most recently, PEX11B was associated with an atypical peroxisome biogenesis disorder (PBD) in a single individual. In this study, we identify further PEX11B cases and delineate associated phenotypes.

Methods: Probands from three families underwent next generation sequencing (NGS) for diagnosis of a multisystem developmental disorder. Autozygosity mapping was conducted in one affected sibling pair. ExomeDepth was used to identify copy number variants from NGS data and confirmed by dosage analysis. Biochemical profiling was used to investigate the metabolic signature of the condition.

Results: All patients presented with bilateral cataract at birth but the systemic phenotype was variable, including short stature, skeletal abnormalities, and dysmorphism-features not described in the original case. Next generation sequencing identified biallelic loss-of-function mutations in PEX11B as the underlying cause of disease in each case (PEX11B c.235C>T p.(Arg79Ter) homozygous; PEX11B c.136C>T p.(Arg46Ter) homozygous; PEX11B c.595C>T p.(Arg199Ter) heterozygous, PEX11B ex1-3 del heterozygous). Biochemical studies identified very low plasmalogens in one patient, whilst a mildly deranged very long chain fatty acid profile was found in another.

Conclusions: Our findings expand the phenotypic spectrum of the condition and underscore congenital cataract as the consistent primary presenting feature. We also find that biochemical measurements of peroxisome function may be disturbed in some cases. Furthermore, diagnosis by NGS is proficient and may circumvent the requirement for an invasive skin biopsy for disease identification from fibroblast cells.
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http://dx.doi.org/10.1167/iovs.16-21026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841568PMC
January 2017

A Comparison of Gait Patterns between Late-Onset Pompe Disease and Age-Matched Healthy Individuals: Does Late-Onset Pompe Disease have a Typical Gait Pattern?

J Neuromuscul Dis 2015;2(s1):S31

School of Healthcare Science, University of Salford, Salford, Manchester, UK.

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January 2015

Reply to Thibault & Genton:.

Clin Nutr 2014 Dec 20;33(6):1158-9. Epub 2014 Aug 20.

Dept. of Medicine, Southern Clinical School, Monash University, Clayton, Victoria, Australia.

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http://dx.doi.org/10.1016/j.clnu.2014.08.008DOI Listing
December 2014

Skeletal muscle mass in hospitalized elderly patients: comparison of measurements by single-frequency BIA and DXA.

Clin Nutr 2014 Jun 18;33(3):426-31. Epub 2013 Jun 18.

Dept. of Medicine, Southern Clinical School, Monash University, Clayton, Victoria, Australia. Electronic address:

Background & Aims: There is increasing interest in estimating skeletal muscle mass (SMM) in clinical practice. We aimed to validate a bioelectrical impedance analysis (BIA) prediction equation for SMM, developed in a different healthy elderly population, in a population of hospital patients aged 70 and over, by comparison with dual-energy X-ray absorptiometry (DXA) SMM estimates. Comparison was also made with two other previously published BIA muscle prediction equations.

Methods: Muscle measurements by BIA and DXA were compared in 117 patients with a range of clinical conditions (45 female, 72 male, mean age 75 years).

Results: The BIA equation used yielded an accurate estimate of DXA-derived SMM. Mean (SD) difference was 0.26(1.79) kg (ns). The two other BIA equations over-estimated SMM compared to DXA (both p < 0.001), but all equations were highly correlated.

Conclusions: The BIA equation used, developed in a different healthy elderly population, gave an accurate estimate of DXA-derived SMM in a population with various clinical disorders. BIA appears potentially capable to estimate SMM in clinical disorders, but the optimal approach to its use for this purpose requires further investigation.
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http://dx.doi.org/10.1016/j.clnu.2013.06.007DOI Listing
June 2014

Fermentation of calcium-fortified soya milk does not appear to enhance acute calcium absorption in osteopenic post-menopausal women.

Br J Nutr 2011 Jan 21;105(2):282-6. Epub 2010 Sep 21.

School of Biomedical and Health Sciences, Victoria University, St Albans Campus, PO Box 14428, Melbourne, VIC 8001, Australia.

Ageing women may choose to drink soya milk to reduce menopausal symptoms. As fermentation enriches soya milk with isoflavone aglycones, its beneficial qualities may improve. To reduce osteoporotic risk, however, soya milk must be Ca enriched, and it is not known how fermentation affects Ca bioavailability. A randomised crossover pilot study was undertaken to compare the Ca absorption of fortified soya milk with that of fermented and fortified soya milk in twelve Australian osteopenic post-menopausal women. The fortified soya milk was inoculated with Lactobacillus acidophilus American Type Culture Collection (ATCC) 4962 and fermented for 24 h at 37°C. Ca absorption from soya milk samples was measured using a single isotope radiocalcium method. Participants had a mean age of 54·8 (sd 12·3) years, with mean BMI of 26·5 (sd 5·5) kg/m2 and subnormal to normal serum 25-hydroxyvitamin D (mean 62·5 (sd 19·1) nmol/l). Participants consumed 185 kBq of 45Ca in 44 mg of Ca carrier. The mean fractional Ca absorption (α) from soya milk and fermented soya milk was 0·64 (sd 0·23) and 0·71 (sd 0·29), respectively, a difference not of statistical significance (P = 0·122). Although fermentation of soya milk may provide other health benefits, fermentation had little effect on acute Ca absorption.
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http://dx.doi.org/10.1017/S0007114510003442DOI Listing
January 2011

Phytase activity from Lactobacillus spp. in calcium-fortified soymilk.

J Food Sci 2010 Aug;75(6):M373-6

School of Biomedical and Health Sciences, Victoria Univ., Melbourne, VIC, Australia.

The presence of phytate in calcium-fortified soymilk may interfere with mineral absorption. Certain lactic acid bacteria (LAB) produce the enzyme phytase that degrades phytates and therefore may potentially improve mineral bioavailability and absorption. This study investigates the phytase activity and phytate degradation potential of 7 strains of LAB including: Lactobacillus acidophilus ATCC4962, ATCC33200, ATCC4356, ATCC4161, L. casei ASCC290, L. plantarum ASCC276, and L. fermentum VRI-003. Activity of these bacteria was examined both in screening media and in calcium-fortified soymilk supplemented with potassium phytate. Most strains produced phytase under both conditions with L. acidophilus ATCC4161 showing the highest activity. Phytase activity in fortified soymilk fermented with L. acidophilus ATCC4962 and L. acidophilus ATCC4161 increased by 85% and 91%, respectively, between 12 h and 24 h of fermentation. All strains expressed peak phytase activity at approximately pH 5. However, no phytate degradation could be observed.
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http://dx.doi.org/10.1111/j.1750-3841.2010.01663.xDOI Listing
August 2010

Calcium absorption in Australian osteopenic post-menopausal women: an acute comparative study of fortified soymilk to cows' milk.

Asia Pac J Clin Nutr 2010 ;19(2):243-9

School of Biomedical and Health Sciences, Victoria University, St Albans Campus, Melbourne, VIC 8001, Australia.

Calcium loss after menopause increases the risk of osteoporosis in aging women. Soymilk is often consumed to reduce menopausal symptoms, although in its native form, it contains significantly less calcium than cow's milk. Moreover, when calcium is added as a fortificant, it may not be absorbed efficiently. This study compares calcium absorption from soymilk fortified with a proprietary phosphate of calcium versus absorption from cow's milk. Preliminary studies compared methods for labelling the calcium fortificant either before or after its addition to soymilk. It was established that fortificant labelled after it was added to soymilk had a tracer distribution pattern very similar to that shown by fortificant labelled before adding to soymilk, provided a heat treatment (90?C for 30 min) was applied. This method was therefore used for further bioavailability studies. Calcium absorption from fortified soy milk compared to cow's milk was examined using a randomised single-blind acute cross-over design study in 12 osteopenic post-menopausal women aged (mean +/- SD) 56.7+/-5.3 years, with a body mass index of 26.5+/-5.6 kg/m2. Participants consumed 20 mL of test milk labelled after addition of fortificant with 185 kBq of 45Ca in 44 mg of calcium carrier, allowing the determination of the hourly fractional calcium absorption rate (alpha) using a single isotope radiocalcium test. The mean hourly fractional calcium absorption from fortified soymilk was found to be comparable to that of cows' milk: alpha = 0.65+/-0.19 and alpha =0.66+/-0.22, p>0.05, respectively.
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July 2010

Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content.

Menopause 2008 Nov-Dec;15(6):1157-62

School of Biomedical and Health Sciences, Victoria University, St. Albans, Victoria, Australia.

Objective: To examine the estrogenic and androgenic activity of Lepidium meyenii (Maca) and its effect on the hormonal profile and symptoms in postmenopausal women.

Design: Fourteen postmenopausal women completed a randomized, double-blind, placebo-controlled, crossover trial. They received 3.5 g/day of powered Maca for 6 weeks and matching placebo for 6 weeks, in either order, over a total of 12 weeks. At baseline and weeks 6 and 12 blood samples were collected for the measurement of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin, and the women completed the Greene Climacteric Scale to assess the severity of menopausal symptoms. In addition, aqueous and methanolic Maca extracts were tested for androgenic and estrogenic activity using a yeast-based hormone-dependent reporter assay.

Results: No differences were seen in serum concentrations of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin between baseline, Maca treatment, and placebo (P > 0.05). The Greene Climacteric Scale revealed a significant reduction in scores in the areas of psychological symptoms, including the subscales for anxiety and depression and sexual dysfunction after Maca consumption compared with both baseline and placebo (P < 0.05). These findings did not correlate with androgenic or alpha-estrogenic activity present in the Maca as no physiologically significant activity was observed in yeast-based assays employing up to 4 mg/mL Maca extract (equivalent to 200 mg/mL Maca).

Conclusions: Preliminary findings show that Lepidium meyenii (Maca) (3.5 g/d) reduces psychological symptoms, including anxiety and depression, and lowers measures of sexual dysfunction in postmenopausal women independent of estrogenic and androgenic activity.
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http://dx.doi.org/10.1097/gme.0b013e3181732953DOI Listing
April 2009

Insulin and insulin resistance.

Authors:
Gisela Wilcox

Clin Biochem Rev 2005 May;26(2):19-39

Melbourne Pathology, Collingwood, VIC 3066, Australia.

As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalization, urbanisation and industrialization have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1204764PMC
May 2005

Bioavailability of isoflavone phytoestrogens in postmenopausal women consuming soya milk fermented with probiotic bifidobacteria.

Br J Nutr 2005 Jun;93(6):867-77

Food Safety Authenticity and Quality Unit, Victoria University, Werribee Campus, Victoria, Australia.

We investigated the effects of consuming an isoflavone aglycone-enriched soya milk containing viable bifidobacteria on urinary isoflavone excretion and percentage recovery. Sixteen postmenopausal women were randomly divided into two groups to consume either fermented or non-fermented soya milk. Each group participated in a double-blind, crossover study with three 14 d supplementation periods, separated by a 14 d washout. Subjects ingested three daily dosages of isoflavone via the soya milk and collected four 24 h pooled urine specimens per supplementation period. Soya milks were prepared with soya protein isolate and soya germ, followed by fermentation with bifidobacteria. Isoflavone levels were quantified using HPLC. Non-fermented soya milks at 20, 40 and 80 mg isoflavone/200 ml contained 10 %, 9 % and 7 % aglycone, respectively, with their fermented counterparts containing 69 %, 57 % and 36 % aglycone (P<0.001). A trend to a greater percentage urinary recovery of daidzein and glycitein was observed among women consuming fermented soya milk at a dosage of 40 mg isoflavone (P=0.13). A distinct linear dose response for the fermented soya milk group (R2=0.9993) compared with the non-fermented group (R2=0.8865) suggested less interindividual variation in isoflavone absorption. However, total urinary isoflavone excretion was similar for both groups (P>0.05), with urinary isoflavone recovery at approximately 31 %. Increasing the isoflavone dosage correlated positively with its urinary excretion, but urinary percentage recovery of isoflavone was inversely related to dosage level. Hence, a modest dosage ranging from 20 to 30 mg/d may provide the most bioavailable source of isoflavone, regardless of whether it is via an aglycone-rich fermented soya milk or a glucoside-rich soya milk.
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http://dx.doi.org/10.1079/bjn20041299DOI Listing
June 2005