Systematic metabolic engineering enables highly efficient production of vitamin A in Saccharomyces cerevisiae.

Vitamin A is a micronutrient critical for versatile biological functions and has been widely used in the food, cosmetics, pharmaceutical, and nutraceutical industries. Synthetic biology and metabolic engineering enable microbes, especially the model organism Saccharomyces cerevisiae (generally recognised as safe) to possess great potential for the production of vitamin A. Herein, we first generated a vitamin A-producing strain by mining ß-carotene 15,15'-mono(di)oxygenase from different sources and identified two isoenzymes Mbblh and Ssbco with comparable catalytic properties but different catalytic mechanisms. Combinational expression of isoenzymes increased the flux from ß-carotene to vitamin A metabolism. To modulate the vitamin A components, retinol dehydrogenase 12 from Homo sapiens was introduced to achieve more than 90 % retinol purity using shake flask fermentation. Overexpressing POS5Δ17 enhanced the reduced nicotinamide adenine dinucleotide phosphate pool, and the titer of vitamin A was elevated by almost 46 %. Multi-copy integration of the key rate-limiting step gene Mbblh further improved the synthesis of vitamin A. Consequently, the titer of vitamin A in the strain harbouring the Ura3 marker was increased to 588 mg/L at the shake-flask level. Eventually, the highest reported titer of 5.21 g/L vitamin A in S. cerevisiae was achieved in a 1-L bioreactor. This study unlocked the potential of S. cerevisiae for synthesising vitamin A in a sustainable and economical way, laying the foundation for the commercial-scale production of bio-based vitamin A.

Keratomalacia and corneal perforation in vitamin A deficiency: Anterior-segment optical-coherence-tomography and histological findings.

Purpose: To describe the histological findings and results of anterior-segment optical-coherence-tomography (AS-OCT) in patients with severe keratomalacia and corneal perforation due to vitamin-A deficiency (VAD). Observations: Four patients (3 female, 1 male) with moderate to severe VAD were included in this single-center case series. Keratomalacia/corneal perforation was diagnosed by slit-lamp examination. The findings were documented using photographs and AS-OCT imaging (CASIA-2, Tomey corporation, Nagoya, Japan). Ocular and general medical findings including causes of VAD are reported. VAD was severe (<20 ng/ml) in two patients with chronic alcoholism, and moderate (205/231 ng/ml) in two patients with cachexia. Corneal perforation occurred in 3 out of 4 patients. One patient had severe keratomalacia with impending perforation and massive conjunctival folds with Bitot's spots, which vanished soon after initiation of vitamin A supplementation. In three cases, corneal specimens obtained during anterior lamellar keratoplasty were assessed histologically by light-microcopy. The histological specimens showed massive epithelial thickening and a pronounced granular layer of the corneal epithelium. Conclusions and importance: Keratomalacia leading to corneal perforation is a rare, but possible complication also in countries with sufficient general food supply. The clinico-pathological correlation between AS-OCT and histological findings in patients with VAD is shown in this case series. Typical Bitot's spots were present only in one patient and can be visualized by AS-OCT.

From ß-Carotene to Retinoids: A Review of Microbial Production of Vitamin A.

Vitamin A (retinoids) is crucial for human health, with significant demand across the food, pharmaceutical, and animal feed industries. Currently, the market primarily relies on chemical synthesis and natural extraction methods, which face challenges such as low synthesis efficiency and complex extraction processes. Advances in synthetic biology have enabled vitamin A biosynthesis using microbial cell factories, offering a promising and sustainable solution to meet the increasing market demands. This review introduces the key enzymes involved in the biosynthesis of vitamin A from ß-carotene, evaluates achievements in vitamin A production using various microbial hosts, and summarizes strategies for optimizing vitamin A biosynthesis. Additionally, we outline the remaining challenges and propose future directions for the biotechnological production of vitamin A.

The Influence of Retinol Ointment on Rabbit Skin (Oryctolagus cuniculus) Ion Transport-An In Vitro Study.

Retinoids are known to improve the condition of the skin. Transepithelial transport of sodium and chloride ions is important for proper skin function. So far, the effect of applying vitamin A preparations to the skin on ion transport has not been evaluated. In the study, electrophysiological parameters, including transepithelial electric potential (PD) and transepithelial resistance (R), of rabbit skin specimens after 24 h exposure to retinol ointment (800 mass units/g) were measured in a modified Ussing chamber. The R of the fragments incubated with retinol was significantly different than that of the control skin samples incubated in iso-osmotic Ringer solution. For the controls, the PD values were negative, whereas the retinol-treated specimens revealed positive PD values. Mechanical-chemical stimulation with the use of inhibitors of the transport of sodium (amiloride) or chloride (bumetanide) ions revealed specific changes in the maximal and minimal PD values measured for the retinol-treated samples. Retinol was shown to slightly modify the transport pathways of sodium and chloride ions. In particular, an intensification of the chloride ion secretion from keratinocytes was observed. The proposed action may contribute to deep hydration and increase skin tightness, limiting the action of other substances on its surface.

Cosmeceuticals in photoaging: A review.

BACKGROUND: Photoaging is a process of the architecture of normal skin damaged by ultraviolet radiation. Topical cosmeceuticals have been used to treat this condition. The authors aimed to understand the mechanism and level of evidence of different commonly used cosmeceuticals used to treat photodamaged skin. OBJECTIVE: A range of commonly used topical cosmeceuticals (botanicals, peptides, and hydroquinone) has been used in cosmetic medicine for many years to treat photodamaged skin. This review article compares their efficacy and level of evidence. MATERIAL AND METHODS: This study was a systematic review to evaluate the efficacy of different topical cosmeceuticals. Keywords including "Photoaging," "Azelaic acid," "Soy," "Green Tea," "Chamomile," "Ginkgo," "Tea Tree Oil," "Resveratrol," "Cucumber," "Ginseng," "Centella asiatica," "Licorice Root," "Aloe Vera," "Peptides," "Argireline," "Hydroquinone," were typed on OVID, PUBMED, MEDLINE for relevant studies published on photoaging treatment. RESULTS: Most of the evidence behind cosmeceuticals is of high-quality ranging from Level I to Level II. In particular, the evidence base behind peptides is the strongest with most studies achieving Level Ib status in the evidence hierarchy. CONCLUSION: Topical cosmeceuticals like botanicals, peptides and hydroquinone can effectively treat photodamaged skin.

Micronutrient deficiencies and the double burden of malnutrition in Vietnamese female adolescents: a national cross-sectional study in 2020.

Background: Vietnam is facing a double burden of malnutrition, with increasing prevalence of overweight coexisting with undernutrition (stunting and/or thinness) and micronutrient deficiencies (MNDs). Although malnutrition during female adolescence leads to poor health outcomes with potential intergenerational effects on offspring, no studies have comprehensively investigated MNDs and nutritional status among contemporary Vietnamese female adolescents. Methods: Data from 10- to 18-year-old female participants (n = 1471) in the nationally-representative Vietnam General Nutrition Survey 2020 were analysed. Blood nutritional biomarkers, anthropometric measurements, and sociodemographic data were collected, and associations between nutrition status and MNDs were analysed; with anaemia, iron deficiency (ID), iron deficiency anaemia, low serum zinc, low serum retinol, and any MNDs as specified outcomes. Findings: Prevalence of overweight, stunting, and thinness was 27.2%, 14.3%, and 6.9%, respectively. Low serum zinc was common (39.8%), as was ID (13.4%). Bivariate analyses showed that older age (16-18 years old), ethnic minority status, lower wealth index, and inflammation were associated with MNDs. In adjusted logistic regressions, stunting was associated with increased odds ratio and [95% confidence intervals] of low serum retinol (8.92 [2.26, 35.15], p < 0.01), as was thinness (12.25 [3.47, 43.33], p < 0.01). Stunting was also associated with increased odds of having any MND (2.06 [1.31, 3.25], p < 0.01). Interpretation: More female adolescents were overweight than undernourished in Vietnam in 2020. However, undernutrition, low serum zinc, and ID remain prevalent. Food systems approaches should be considered to stem the stark increase in the double burden of malnutrition in young people living in Vietnam. Funding: UK BBSRCBB/T008989/1.

Association of vitamin A with gestational diabetes and thyroid disorders in pregnancy and their influence on maternal, fetal, and neonatal outcomes.

Gestational diabetes mellitus (GDM) and thyroid disorders during pregnancy pose significant health concerns, impacting a substantial number of mothers globally. Globally, about 14% of pregnant women develop GDM, while thyroid disorders impact approximately 2%-3%. Both conditions contribute to adverse outcomes, including gestational hypertension, excessive fetal growth, and heightened perinatal morbidity. The central focus of this literature review is to examine the relationship between vitamin A, a crucial fat-soluble micronutrient in fetal development, and the occurrence of GDM and thyroid disorders during pregnancy. The primary research question investigates the association between vitamin A, GDM, and thyroid disorders, analyzing their combined impact on maternal, fetal, and neonatal outcomes. The review underscores the potential of vitamin A to modulate the risk and outcomes of GDM and thyroid disorders during gestation, emphasizing its role in GDM development and resolution and its influence on thyroid function in pregnancy.

Nyctalopia during pregnancy due to vitamin A deficiency after bariatric sleeve gastrectomy: A case report.

Key Clinical Message: Herein, we report a rare case of nyctalopia diagnosed in the first trimester of pregnancy due to vitamin A deficiency as a result of a bariatric gastrectomy. Low serum vitamin A levels establish the diagnosis and the patient was treated with oral vitamin A supplements. Moreover, due to the teratogenic effects of exceed Vitamin A levels in early pregnancy, supplements' dosages should be prescribed with respect to the safe limits. Our case aims to highlight the importance of checking micronutricients and vitamins levels before and during pregnancy in women that had a previous bariatric surgery. Abstract: Vitamin A deficiency (VAD) has been identified as the predominant factor in the development of night blindness during pregnancy, a high-risk for morbidity situation. Herein, we report a rare case of nyctalopia diagnosed in the first trimester of pregnancy due to VAD as a result of a bariatric gastrectomy. Our case aims to highlight the importance of checking micronutricients and vitamins levels before and during pregnancy in women that had a previous bariatric surgery. Low serum vitamin A levels establish the diagnosis and the patient was treated with oral vitamin A supplements. An uneventful antenatal course resulted in the birth of a healthy live neonatal at 38 weeks of gestation. In conclusion, nyctalopia is a rare condition in pregnant women that is often caused by VAD that poses significant health risks for both the mother and the infant, especially in women with a history of gastrointestinal bypass surgery, or any factors leading to malnutrition. Clinicians have to be alerted for micronutrients deficient in pregnant women who have a bariatric operation in their medical history.

Evaluation of developmental milestones and of brain measurements in rats exposed to the pesticide pyriproxyfen in prenatal period.

Pyriproxyfen is a pesticide used in Brazil to control the Aedes aegypti mosquito, vector of arboviruses like Zika and dengue. However, this pesticide is structurally similar to retinoic acid, a metabolite of vitamin A that regulates neuronal differentiation and hindbrain development during the embryonic period. Due to the similarity between pyriproxyfen and retinoic acid, studies indicate that this pesticide may have cross-reactivity with retinoid receptors. Thus, pregnant exposure to pyriproxyfen could interfere in the nervous system development of the fetal. In this context, the present study evaluated whether prenatal exposure to pyriproxyfen affects neonatal development and brain structure in rats. Wistar rat pups were divided in three experimental groups: (1) negative control (CT-)-offspring of rats that drink potable water during pregnancy; (2) pyriproxyfen (PIR)-offspring of rats exposed to Sumilarv® prenatally, a pesticide that has pyriproxyfen as active ingredient; and (3) positive control (CT+)-offspring of rats exposed to an excess of vitamin A prenatally. Only vitamin A treated-pregnant showed lower weight gain, but gestation length was similar among pregnant that received potable water, water containing vitamin A and water containing Sumilarv. In relation to the offspring, PIR group exhibits a delayed front-limb suspension response but performed early the negative geotaxis reflex. On the other hand, CT+ group exhibited lower body weight in the 1st postnatal day, delayed audio startle response, but performed early the eyelids opening and hindlimb placing response. A reduction in the maximum brain width was observed both in PIR and CT+ groups, but a reduction in the number of neurons in the M1 cortex was showed only in CT+ group. The number of glial cells in this brain area was similar between the three experimental groups studied. Although prenatal exposure to pyriproxyfen did not alter neonatal milestones in the same way as vitamin A in excess, both substances caused a reduction in the maximum width of the brain, suggesting that this pesticide can produce neurotoxic effects during the embryonic period.

Malnutrition and Allergies: Tipping the Immune Balance towards Health.

Malnutrition, which includes macro- and micronutrient deficiencies, is common in individuals with allergic dermatitis, food allergies, rhinitis, and asthma. Prolonged deficiencies of proteins, minerals, and vitamins promote Th2 inflammation, setting the stage for allergic sensitization. Consequently, malnutrition, which includes micronutrient deficiencies, fosters the development of allergies, while an adequate supply of micronutrients promotes immune cells with regulatory and tolerogenic phenotypes. As protein and micronutrient deficiencies mimic an infection, the body's innate response limits access to these nutrients by reducing their dietary absorption. This review highlights our current understanding of the physiological functions of allergenic proteins, iron, and vitamin A, particularly regarding their reduced bioavailability under inflamed conditions, necessitating different dietary approaches to improve their absorption. Additionally, the role of most allergens as nutrient binders and their involvement in nutritional immunity will be briefly summarized. Their ability to bind nutrients and their close association with immune cells can trigger exaggerated immune responses and allergies in individuals with deficiencies. However, in nutrient-rich conditions, these allergens can also provide nutrients to immune cells and promote health.

Evaluating the Protective Role of Vitamin A Supplementation in Periodontal Health: A Comprehensive Systematic Review and Meta-Analysis.

Background: Recent studies suggest a potential role for vitamin A supplementation in improving periodontal health, though evidence remains inconclusive. This systematic review and meta-analysis aimed to evaluate the protective role of vitamin A supplementation on periodontal health, focusing on outcomes such as gingival inflammation, pocket depth reduction, and alveolar bone preservation. Methods: A literature search was conducted in PubMed, Scopus, and Web of Science up until May 2024, adhering to strict inclusion criteria that required studies to involve human participants diagnosed with periodontal diseases and to assess the impact of vitamin A through dietary intake or supplementation. This review excluded studies not explicitly focused on vitamin A and those lacking clear, quantifiable outcomes. The risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Collaboration's tool for randomized controlled trials. Meta-analysis was performed to synthesize data and quantify the effectiveness of vitamin A on periodontal health outcomes. Results: A total of six studies were included in the final analysis with a total of 50,722 participants. The meta-analysis revealed a pooled odds ratio (OR) of 0.97 (95% CI: 0.94-1.00) for the association between vitamin A supplementation and periodontal health, indicating a slight protective effect. Notably, two high-quality studies reported ORs of 0.92 (95% CI: 0.85-1.00) and 0.83 (95% CI: 0.69-1.00), respectively, suggesting a potential reduction in periodontal disease risk with sufficient vitamin A levels. However, high heterogeneity (I2 = 86.93%) across studies indicates variability in outcomes, possibly influenced by demographic and lifestyle factors. Conclusions: Vitamin A supplementation may offer a marginal protective effect against periodontal disease, although results vary significantly across different populations and study designs. Further research is needed to clarify these relationships and to explore the mechanisms through which vitamin A influences periodontal health, considering the high degree of observed heterogeneity.

Vitamin A supplementation status and associated factors among children aged 6-59 months in Tanzania: a multi-level analysis.

Background: Vitamin A supplementation every 4-6 months is an economical, rapid, and effective strategy to enhance vitamin A status and minimize child morbidity and mortality due to vitamin A deficiency in the long run. Therefore, this study was aimed at investigating the level as well as the factors influencing VAS status among children aged 6-59 months in Tanzania. Methods: This analysis relied on data from the 2022 Tanzania Demographic and Health Survey (TDHS). The study used a weighted sample of 9,382 children aged 6-59 months. Given the effect of clustering and the binary character of the outcome variable, we employed a multilevel binary logistic regression model. The adjusted odds ratio (AOR) with a 95% confidence interval (CI) was used to determine statistical significance, considering the model with the lowest deviation that best fits the data. Results: In this study, vitamin A supplementation among children aged 6-59 months was found to be 53.18% [95% CI: 52.17, 54.19]. Mother's/caregiver's working status; Working [AOR = 1.59, 95% CI: 1.34, 1.89], ANC follow-up [AOR = 1.71, 95%CI: 1.34, 2.2], and health facility delivery [AOR = 1.55, 95%CI: 1.25, 1.91] were individual-level factors associated with vitamin A supplementation. Whereas administrative zones of Western [AOR = 2.02, 95% CI: 1.16, 3.52], Southern highlands [AOR = 3.83, 95% CI: 2.02, 7.24], Southern administrative zone [AOR = 2.69, 95% CI: 1.37, 5.3], and South West highlands [AOR = 0.56, 95% CI: 0.33, 0.95] were community-level factors associated with vitamin A supplementation. Conclusion: The proportion of VAS among children in Tanzania is low compared to UNICEF's target of 80. Mother's/caregiver's working status, antenatal care, place of delivery, community-level media exposure, and administrative zones were significantly associated factors with vitamin A supplementation. Therefore, interventions should be designed to improve the uptake of VAS. Provision and promotion of ANC and institutional delivery and strengthening of routine supplementation are recommended to increase coverage of childhood vitamin A supplementation. Moreover, special focus should be given to regions in the south-western highlands.

Retinoids: Molecular Aspects and Treatment in Premalignant Lesions and Cervical Cancer.

Persistent infection with high-risk human papillomavirus remains the primary factor associated with the progression of cervical squamous intraepithelial lesions and the development of cervical cancer. Nevertheless, a combination of factors, including genetic predisposition, immune response, hormonal influences, and nutritional status, contribute synergistically to the development of cervical cancer. Among the various factors involved in the pathogenesis and therapy of cervical cancer, retinoids have gained considerable attention due to their multifaceted roles in different cellular processes. This review investigates defects within the vitamin A metabolism pathway and their correlation with cervical cancer. Additionally, it integrates epidemiological and experimental findings to discuss the potential utility of retinoid-based therapies, either alone or combined with other therapies, as agents against premalignant lesions and cervical cancer.

Vitamin A carotenoids, but not retinoids, mediate the impact of a healthy diet on gut microbial diversity.

BACKGROUND: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). METHODS: We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. RESULTS: Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p < 4 × 10-6). Carotenoid compounds were positively correlated with the short-chain fatty-acid-producing bacteria Faecalibacterium prausnitzii and Coprococcus eutactus. Retinol was not associated with any microbial species. We found that gut microbiome composition could predict circulating levels of carotenoids and oxoretinoic acid with AUCs ranging from 0.66 to 0.74 using random forest models, but not retinol (AUC = 0.52). The healthy eating index (HEI) was strongly associated with gut microbiome diversity and with all carotenoid compounds, but not retinoids. We investigated the mediating role of carotenoid compounds on the effect of a healthy diet (HEI) on gut microbiome diversity, finding that carotenoids significantly mediated between 18 and 25% of the effect of HEI on gut microbiome alpha diversity. CONCLUSIONS: Our results show strong links between circulating carotene compounds and gut microbiome composition and potential links to a healthy diet pattern.

Boosting pro-vitamin A content and bioaccessibility in leaves by combining engineered biosynthesis and storage pathways with high-light treatments.

Biofortification of green leafy vegetables with pro-vitamin A carotenoids, such as ß-carotene, has remained challenging to date. Here, we combined two strategies to achieve this goal. One of them involves producing ß-carotene in the cytosol of leaf cells to avoid the negative impacts on photosynthesis derived from changing the balance of carotenoids and chlorophylls in chloroplasts. The second approach involves the conversion of chloroplasts into non-photosynthetic, carotenoid-overaccumulating chromoplasts in leaves agroinfiltrated or infected with constructs encoding the bacterial phytoene synthase crtB, leaving other non-engineered leaves of the plant to sustain normal growth. A combination of these two strategies, referred to as strategy C (for cytosolic production) and strategy P (for plastid conversion mediated by crtB), resulted in a 5-fold increase in the amount of ß-carotene in Nicotiana benthamiana leaves. Following several attempts to further improve ß-carotene leaf contents by metabolic engineering, hormone treatments and genetic screenings, it was found that promoting the proliferation of plastoglobules with increased light-intensity treatments not only improved ß-carotene accumulation but it also resulted in a much higher bioaccessibility. The combination of strategies C and P together with a more intense light treatment increased the levels of accessible ß-carotene 30-fold compared to controls. We further demonstrated that stimulating plastoglobule proliferation with strategy P, but also with a higher-light treatment alone, also improved ß-carotene contents and bioaccessibility in edible lettuce (Lactuca sativa) leaves.

Enhancing vitamin A stability using saponin-chitosan polyelectrolytes coating: Optimization, haracterization, and controlled release.

Microencapsulation has the potential to address the stability issues associated with vitamin A. This study examined the effectiveness of emulsifying a saponin-chitosan polyelectrolyte complex to encapsulate vitamin A. Utilizing response surface methodology (RSM), the effects of the chitosan, saponin, and vitamin A contents on various response variables were measured to optimize the formulation. The optimized emulsion was characterized through fluorescence microscopy, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), storage stability, and release profile. Fluorescence microscopy showed that vitamin A was evenly distributed throughout the optimized emulsion. The polyelectrolyte complex and vitamin A were shown to interact hydrophobically and electrostatically by FTIR analysis. The DSC results verified the effective encapsulation and showed that vitamin A heat stability had been enhanced. Study on storage stability demonstrated that during a 2-month storage period, the encapsulated vitamin A remained stable. Moreover, vitamin A was significantly released from the encapsulated form at pH 1.2, based on release assays. In conclusion, saponin-chitosan polyelectrolyte coating proved to be a potentially useful new material for the stability and applications of vitamin A in a range of formulations.

Association between vitamin A supplementation and stunting and anemia in socially vulnerable Brazilian children.

PURPOSE: Vitamin A is related to concentrations of insulin-like growth factor type 1, a protein produced in response to growth hormone, and to increased mobilization of body iron stores. Thus, vitamin A aids in increased hematopoiesis and may be useful in preventing stunting and anemia. This study aimed to identify the association between vitamin A supplementation from the National Vitamin A Supplementation Program instituted in Brazil and stunting and anemia in socially vulnerable Brazilian children. METHODS: This is a Cross-sectional population-based study. Children aged 6-59 months old, living in favelas of a capital city in the Northeast of Brazil, were included. Sociodemographic variables were collected. Vitamin A supplementation was also evaluated using the child's vaccination card information. Anthropometric and capillary hemoglobin evaluations were performed to identify the presence of stunting and anemia, respectively. The association analysis was performed using Poisson regression with robust variance estimation. RESULTS: 598 children participated in this study; 11.3% and 55.6% had stunting and anemia, respectively. As for vitamin A supplementation, 59.5% had taken at least one dose of the supplement,and 3.5% were on the complete supplementation scheme. In the adjusted association analysis, vitamin A supplementation decreased the likelihood of children having stunting and anemia by 8% (RP:0.86; 95% IC 0.86-0.98; p = 0.014) and 31% (RP:0.69; 95% IC 0.53-0.89; p = 0.004), respectively. Children who were fully supplemented were 58% (RP:0.42; 95% IC 0.24-0.77; p = 0.008) less likely to have anemia. CONCLUSION: Thus, vitamin A supplementation is a protective tool against stunting and anemia in children living in a situation of social vulnerability.

Disentangling discordant vitamin D associations with prostate cancer incidence and fatality in a large, nested case-control study.

BACKGROUND: Published analyses of prostate cancer nested case-control and survival data in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort suggested that men with higher baseline vitamin D [25(OH)D] concentrations have both (i) increased prostate cancer risk and (ii) decreased prostate cancer-specific fatality. METHODS: To investigate possible factors responsible for a spurious association with prostate cancer fatality, we reanalysed baseline serum vitamin D associations with prostate cancer risk and prostate cancer-specific fatality in case-control data nested within the ATBC Study (1000 controls and 1000 incident prostate cancer cases). Conditional logistic regression and Cox proportion hazard models were used, respectively, to estimate odds ratios for risk and hazard ratios for prostate cancer-specific fatality, overall and by disease aggressiveness. We replicated these case-control analyses using baseline serum measurements of alpha-tocopherol (vitamin E), beta-carotene and retinol (vitamin A), and used the entire ATBC Study cohort (n = 29 085) to estimate marginal associations between these baseline vitamins and prostate cancer incidence and fatality following blood collection. RESULTS: Vitamin D analyses agreed closely with those originally published, with opposite risk and fatality associations. By contrast, the analyses of alpha-tocopherol, beta-carotene and retinol yielded concordant associations for prostate cancer incidence and prostate cancer-specific fatality. CONCLUSIONS: We found evidence of neither artefacts in the nested prostate cancer case-control data set nor detection or collider biases in the fatality analyses. The present findings therefore support a valid inverse (i.e. beneficial) association between vitamin D and prostate cancer-specific survival that warrants further evaluation, including possibly in controlled trials.

Use of the Paired Retinol Isotope Dilution Test, but with a Single Isotope Dose, to Assess the Impact of a Vitamin A Intervention on Vitamin A Stores in Theoretical Children with Low Stores.

BACKGROUND: As currently applied, the paired retinol isotope dilution (RID) test, which is used to assess the impact of a vitamin A intervention on vitamin A total body stores (TBS), requires 2 doses of stable isotope-labeled vitamin A. OBJECTIVES: The objectives of this study were to evaluate use of a single isotope dose (4 µmol) to assess TBS by RID before and after intervention in theoretical children with low/moderate TBS. METHODS: We selected 6 theoretical children with assigned values for TBS ranging from 82 to 281 µmol. Using Simulation, Analysis and Modeling software, we simulated the variable [plasma retinol specific activity (SAp)] and coefficients (Fa and S) used in the RID equation TBS (µmol) = FaS × 1/SAp in both the unsupplemented steady state at day 14 postdosing and during the subsequent 4 mo without or with vitamin A supplementation [2.8 µmol retinol/d (801 µg retinol activity equivalents/d)]. RESULTS: Fraction of dose in plasma on day 150 compared with day 14 was similar in the unsupplemented and supplemented conditions [geometric mean, 32% (range, 20%-48%) and 30% (20%-48%), respectively] and simulated values for FaS were similar under the 2 conditions. After 2 and 4 mo of daily vitamin A supplementation with 2.8 µmol/d, TBS was 78% and 128% higher, respectively, than without supplementation. CONCLUSIONS: Results indicate that the paired RID method can successfully be done using a single 4 µmol dose of stable isotope. Furthermore, because values for the RID coefficient FaS were similar in the unsupplemented and vitamin A-supplemented conditions, these results in theoretical children indicate that FaS determined by population ("super-subject") modeling of steady state vitamin A kinetic data could be used to predict TBS by RID after a vitamin A intervention in individuals from the same or a similar group.