Clinical, biochemical and molecular analysis in a cohort of individuals with gyrate atrophy.

BACKGROUND: Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic variants in the OAT gene, encoding the enzyme ornithine δ-aminotransferase. Impaired enzymatic activity leads to systemic hyperornithinaemia, which in turn underlies progressive chorioretinal degeneration. In this study, we describe the clinical and molecular findings in a cohort of individuals with gyrate atrophy. METHODS: Study participants were recruited through a tertiary UK clinical ophthalmic genetic service. All cases had a biochemical and molecular diagnosis of gyrate atrophy. Retrospective phenotypic and biochemical data were collected using electronic healthcare records. RESULTS: 18 affected individuals from 12 families (8 male, 10 female) met the study inclusion criteria. The median age at diagnosis was 8 years (range 10 months - 33 years) and all cases had hyperornithinaemia (median: 800 micromoles/L; range: 458-1244 micromoles/L). Common features at presentation included high myopia (10/18) and nyctalopia (5/18). Ophthalmic findings were present in all study participants who were above the age of 6 years. One third of patients had co-existing macular oedema and two thirds developed pre-senile cataracts. Compliance with dietary modifications was suboptimal in most cases. A subset of participants had extraocular features including a trend towards reduced fat-free mass and developmental delay. CONCLUSIONS: Our findings highlight the importance of multidisciplinary care in families with gyrate atrophy. Secondary ophthalmic complications such as macular oedema and cataract formation are common. Management of affected individuals remains challenging due to the highly restrictive nature of the recommended diet and the limited evidence-base for current strategies.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Mental health diagnoses in adults with phenylketonuria: a retrospective systematic audit in a large UK single centre.

BACKGROUND: Recently published European Society for Phenylketonuria (ESPKU) guidelines have recommended a lifelong diet with phenylalanine (Phe) control ≤ 600 µmol/L for phenylketonuria (PKU) patients. This study aimed to identify whether PKU adult patients are at a higher risk of mental health diagnoses if their 2-year average Phe level is higher than the ESPKU European guidelines. Published studies identified by a literature review showed that related studies have been published in American and European PKU study populations but not in the United Kingdom (UK) study populations. Previous studies also involved a smaller number of participants due to this being a rare disease. RESULTS: We undertook a retrospective audit at a single large PKU centre in the UK. 244 adult PKU patients at the centre were included, 220 of which had a recorded Phe level. Approximately 75% of the patients in this study did not meet the ESPKU European guidelines for Phe control. A systematic search of the electronic patient record was undertaken looking for mental health diagnoses. Compared to two-year average Phe levels ≤ 600 µmol/L, PKU adult patients with two-year average Phe levels > 600 µmol/L were more likely to have diagnoses of low mood, depression, anxiety, or mood swings, but only low mood reached statistical significance (p < 0.05). CONCLUSIONS: PKU patients with two-year average Phenylalanine levels greater than ESPKU guidelines may be at greater risk of mental health diagnoses and symptoms. Many of these adult PKU patients will be lost to follow-up, and therefore may be receiving treatment for mental health conditions in the community. Multicentre UK studies and international collaborations are required to overcome low participant numbers in the study of this rare disease.

A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials.

INTRODUCTION: Current clinical outcome assessments (COAs) are not effectively capturing the complex array of symptoms of adults with phenylketonuria (PKU). This study aimed to identify concepts of interest relevant to adults with PKU. Based on these concepts, COAs for patient-reported outcomes (PROs), observer-reported outcomes (ObsROs), and clinician-reported outcomes (ClinROs) were selected or developed and content validity was assessed. MATERIALS AND METHODS: Concept-elicitation interviews were conducted with an international cohort of adults with PKU (n = 30), family member observers (n = 14), and clinical experts (n = 8). Observers and clinical experts were included to overcome the risk of lack of self-awareness among adults with PKU. The concepts of interests endorsed by ≥30% of patients, observers, and/or clinical experts were selected, mapped to items in existing COAs, and used to develop global impression items for patients, observers, and clinicians. Next, the content validity of the COAs and global impression items was evaluated by cognitive interviews with patients (n = 22), observers (n = 11), and clinical experts (n = 8). All patients were categorized according to blood phenylalanine (Phe) levels (i.e., <600 µmol/L, 600-1200 µmol/L, and >1200 µmol/L). RESULTS: Concepts of interests were identified across four domains: emotional, cognitive, physical, and behavioral. After mapping, eight existing COAs were selected based on the concept coverage (six PROs, one ObsRO, and one ClinRO). The six PRO measures were considered as potentially fit-for-purpose. The ObsRO measure was not deemed relevant for use in observers of adults with PKU and only a subscale of the ClinRO measure was considered valid for assessing adults with PKU by clinicians. Due to the lack of existing COAs covering all concepts of interests, global impression items for symptom severity and change in symptoms were developed, which were limited to one question covering in total 14 concepts. Upon validation, some of the patient and observer global impression items were excluded as they were subject to lack of insight or could not be reported by observers. Due to the limited interaction time between clinician and patient, use of the clinician global impression items was not supported. CONCLUSION: Existing COAs relevant to adults with PKU were selected and PKU-specific global impression items were developed by mapping the most frequently identified concepts of interests from internationally-conducted in-depth interviews. Future studies should address the appropriateness of the selected COAs and global impression items to assess if these can be used as efficacy endpoints in PKU clinical trials.

A Three-Year Longitudinal Study Comparing Bone Mass, Density, and Geometry Measured by DXA, pQCT, and Bone Turnover Markers in Children with PKU Taking L-Amino Acid or Glycomacropeptide Protein Substitutes.

In patients with phenylketonuria (PKU), treated by diet therapy only, evidence suggests that areal bone mineral density (BMDa) is within the normal clinical reference range but is below the population norm. AIMS: To study longitudinal bone density, mass, and geometry over 36 months in children with PKU taking either amino acid (L-AA) or casein glycomacropeptide substitutes (CGMP-AA) as their main protein source. METHODOLOGY: A total of 48 subjects completed the study, 19 subjects in the L-AA group (median age 11.1, range 5-16 years) and 29 subjects in the CGMP-AA group (median age 8.3, range 5-16 years). The CGMP-AA was further divided into two groups, CGMP100 (median age 9.2, range 5-16 years) (n = 13), children taking CGMP-AA only and CGMP50 (median age 7.3, range 5-15 years) (n = 16), children taking a combination of CGMP-AA and L-AA. Dual X-ray absorptiometry (DXA) was measured at enrolment and 36 months, peripheral quantitative computer tomography (pQCT) at 36 months only, and serum blood and urine bone turnover markers (BTM) and blood bone biochemistry at enrolment, 6, 12, and 36 months. RESULTS: No statistically significant differences were found between the three groups for DXA outcome parameters, i.e., BMDa (L2-L4 BMDa g/cm2), bone mineral apparent density (L2-L4 BMAD g/cm3) and total body less head BMDa (TBLH g/cm2). All blood biochemistry markers were within the reference ranges, and BTM showed active bone turnover with a trend for BTM to decrease with increasing age. CONCLUSIONS: Bone density was clinically normal, although the median z scores were below the population mean. BTM showed active bone turnover and blood biochemistry was within the reference ranges. There appeared to be no advantage to bone density, mass, or geometry from taking a macropeptide-based protein substitute as compared with L-AAs.

Growth and Body Composition in PKU Children-A Three-Year Prospective Study Comparing the Effects of L-Amino Acid to Glycomacropeptide Protein Substitutes.

Protein quality and quantity are important factors in determining lean body (muscle) mass (LBM). In phenylketonuria (PKU), protein substitutes provide most of the nitrogen, either as amino acids (AA) or glycomacropeptide with supplementary amino acids (CGMP-AA). Body composition and growth are important indicators of long-term health. In a 3-year prospective study comparing the impact of AA and CGMP-AA on body composition and growth in PKU, 48 children were recruited. N = 19 (median age 11.1 years, range 5-15 years) took AA only, n = 16 (median age 7.3 years, range 5-15 years) took a combination of CGMP-AA and AA, (CGMP50) and 13 children (median age 9.2 years, range 5-16 years) took CGMP-AA only (CGMP100). A dual energy X-ray absorptiometry (DXA) scan at enrolment and 36 months measured LBM, % body fat (%BF) and fat mass (FM). Height was measured at enrolment, 12, 24 and 36 months. No correlation or statistically significant differences (after adjusting for age, gender, puberty and phenylalanine blood concentrations) were found between the three groups for LBM, %BF, FM and height. The change in height z scores, (AA 0, CGMP50 +0.4 and CGMP100 +0.7) showed a trend that children in the CGMP100 group were taller, had improved LBM with decreased FM and % BF but this was not statistically significant. There appeared to be no advantage of CGMP-AA compared to AA on body composition after 3-years of follow-up. Although statistically significant differences were not reached, a trend towards improved body composition was observed with CGMP-AA when it provided the entire protein substitute requirement.

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

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

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.

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

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.

Impact of pregnancy on inborn errors of metabolism.

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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.

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.

Insulin and insulin resistance.

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.