Conundrum Abstracts 1

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The conundrum of folate and colorectal cancer (CRC) risk.
            (Arasaradnam, 2010) Download
Folate seems protective against initiation of carcinogenesis, but also promotes carcinogenesis - for example, increase in mortality from breast cancer during pregnancy with folate supplementation.

Plant thioredoxins: the multiplicity conundrum.
            (Baumann and Juttner, 2002) Download
Thioredoxins are small proteins distinguished by the presence of a conserved dicysteine active site. In oxidized thioredoxin, the two cysteines form a disulfide bond that is targeted by the enzyme thioredoxin reductase. Together with an electron donor, thioredoxin and thioredoxin reductase form the 'thioredoxin system' that is present in all organisms. Thioredoxins participate in dithiol/disulfide exchange reactions with a large range of cellular substrates. Higher plants possess a very complex thioredoxin profile consisting of at least two different thioredoxin systems that contain distinct, multigenic thioredoxin classes which have different intracellular localizations. In this review we summarise the current state of knowledge regarding the function of plant thioredoxins representing all systems and classes.

Pyridoxine-dependent seizures: a clinical and biochemical conundrum.
            (Baxter, 2003) Download
Pyridoxine-dependent seizures have been recognised for 40 years, but the clinical and biochemical features are still not understood. It is a rare recessively inherited condition where classically a baby starts convulsing in utero and continues to do so after birth, until given pyridoxine. Many of these early onset cases also have an acute encephalopathy and other clinical features. Late onset cases are now recognised with a less severe form of the condition. Seizures can break through with intercurrent illness but otherwise remain controlled on pharmacologic doses of pyridoxine. The long-term outcome is affected by several factors including whether onset is early or late and how soon pyridoxine is given. Biochemical studies have been sparse, on very small numbers. There does not appear to be any defect in the uptake or metabolism of pyridoxine or pyridoxal phosphate (PLP). For a long time glutamic acid decarboxylase (GAD), a pyridoxal-dependent enzyme, has been suspected to be the abnormal gene product, but glutamate and gamma-aminobutyric acid (GABA) studies on the cerebrospinal fluid (CSF) have been contradictory and recent genetic studies have not found any linkage to the two brain isoforms. A recent report describes raised pipecolic acid levels in patients but how this ties in is unexplained.

The Glutathione Conundrum: Stoichiometric Disconnect between Its Formation and Oxidative Stress.
            (Boysen, 2017) Download
Glutathione (GSH) is the most abundant antioxidant and is believed to maintain redox potential in tissues, cells, and individual compartments. However, GSH concentrations in some tumor cells and tissues have been reported to be as high as 1-10 mM, a concentration that is up to 10,000-fold higher than that of reactive oxygen species. Critical quantitative evaluation of glutathione's proposed functions suggests that glutathione is an amino acid checkpoint. In this role, glutathione contributes to regulating cell proliferation and apoptosis, pending amino acid availability.

Could the gut microbiota reconcile the oral bioavailability conundrum of traditional herbs
            (Chen et al., 2016) Download
ETHNOPHARMACOLOGICAL RELEVANCE:  A wealth of information is emerging about the impact of gut microbiota on human health and diseases such as cardiovascular diseases, obesity and diabetes. As we learn more, we find out the gut microbiota has the potential as new territory for drug targeting. Some novel therapeutic approaches could be developed through reshaping the commensal microbial structure using combinations of different agents. The gut microbiota also affects drug metabolism, directly and indirectly, particularly towards the orally administered drugs. Herbal products have become the basis of traditional medicines such as traditional Chinese medicine and also been being considered valuable materials in modern drug discovery. Of note, low oral bioavailability but high bioactivity is a conundrum not yet solved for some herbs. Since most of herbal products are orally administered, the herbs' constituents are inevitably exposed to the intestinal microbiota and the interplays between herbal constituents and gut microbiota are expected. Emerging explorations of herb-microbiota interactions have an opportunity to revolutionize the way we view herbal therapeutics. The present review aims to provide information regarding the health promotion and/or disease prevention by the interplay between traditional herbs with low bioavailability and gut microbiota through gut microbiota via two different types of mechanisms: (1) influencing the composition of gut microbiota by herbs and (2) metabolic reactions of herbal constituents by gut microbiota. MATERIALS AND METHODS:  The major data bases (PubMed and Web of Science) were searched using "gut microbiota", "intestinal microbiota", "gut flora", "intestinal flora", "gut microflora", "intestinal microflora", "herb", "Chinese medicine", "traditional medicine", or "herbal medicine" as keywords to find out studies regarding herb-microbiota interactions. The Chinese Pharmacopoeia (2010 edition, Volume I) was also used to collect the data of commonly used medicinal herbs and their quality control approaches. RESULTS:  Among the 474 monographs of herbs usually used in the Chinese Pharmacopoeia, the quality control approach of 284 monographs is recommended to use high-performance liquid chromatography approach. Notably, the major marker compounds (>60%) for quality control are polyphenols, polysaccharides and saponins, with significant oral bioavailability conundrum. Results from preclinical and clinical studies on herb-microbiota interactions showed that traditional herbs could exert heath promotion and disease prevention roles via influencing the gut microbiota structure. On the other hand, herb constituents such as ginsenoside C-K, hesperidin, baicalin, daidzin and glycyrrhizin could exert their therapeutic effects through gut microbiota-mediated bioconversion. CONCLUSIONS:  Herb-microbiota interaction studies provide novel mechanistic understanding of the traditional herbs that exhibit poor oral bioavailability. "Microbiota availability" could be taken consideration into describing biological measurements in the therapeutic assessment of herbal medicine. Our review should be of value in stimulating discussions among the scientific community on this relevant theme and prompting more efforts to complement herb-microbiota interactions studies.

Neuronal vs glial glutamate uptake: Resolving the conundrum.
            (Danbolt et al., 2016) Download
Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.

Vitamin D-binding protein as it is understood in 2016: is it a critical key with which to help to solve the calcitriol conundrum
            (Davey, 2017) Download
Background The misnamed 'vitamin' D is actually the hormone calcitriol (1,25 dihydroxyhydroxyvitamin D). It has a central regulatory role in calcium metabolism, and more widely in the immune system. The prohormone calcifediol (25 hydroxyvitamin D) is more easily measured in the laboratory and is the analyte used in reference interval formulation. Being highly lipid soluble, both calcifediol and calcitriol travel in the bloodstream on carriage proteins, principally on vitamin D-binding protein. Summary This review reports our current understanding of vitamin D-binding protein. Its genetic determinants and their effect on it and secondarily on calcifediol concentrations and assays are described. Its complex interplay with parathyroid hormone is considered. The analytical state of the art is translated into the challenge it imposes clinically, in the formulation of reference intervals and in their use in advising and managing patients. Several recent challenges thrown up to laboratories by percipient clinicians highlight the dilemma vitamin D-binding protein poses. A way forward is suggested.

Parkinson disease: Low vitamin D and Parkinson disease--a causal conundrum.
            (Evatt, 2014) Download
Increasing evidence suggests that Parkinson disease (PD) should be included on the growing list of diseases associated with vitamin D insufficiency. A recent study reconfirms this association and supports the monitoring of vitamin D concentrations in patients with PD. The conundrum of causality regarding this association, however, remains unanswered.

Carbohydrate Elimination or Adaptation Diet for Symptoms of Intestinal Discomfort in IBD: Rationales for "Gibsons' Conundrum".
            (Fung and Szilagyi, 2012) Download
THERAPEUTIC USE OF CARBOHYDRATES IN INFLAMMATORY BOWEL DISEASES (IBDS) IS DISCUSSED FROM TWO THEORETICAL, APPARENT DIAMETRICALLY OPPOSITE PERSPECTIVES: regular ingestion of prebiotics or withdrawal of virtually all carbohydrate components. Pathogenesis of IBD is discussed connecting microbial flora, host immunity, and genetic interactions. The best studied genetic example, NOD2 in Crohn's disease, is highlighted as a model which encompasses these interactions and has been shown to depend on butyrate for normal function. The role of these opposing concepts in management of irritable bowel syndrome (IBS) is contrasted with what is known in IBD. The conclusion reached is that, while both approaches may alleviate symptoms in both IBS and IBD, there is insufficient data yet to determine whether both approaches lead to equivalent bacterial effects in mollifying the immune system. This is particularly relevant in IBD. As such, caution is urged to use long-term carbohydrate withdrawal in IBD in remission to control IBS-like symptoms.


 

Vitamin D and falls - the dosage conundrum.
            (Gallagher, 2016) Download
Falls are a major health problem in elderly individuals. Although intensive physical therapy and management of hazards in the home can reduce falls by 25%, long-term practicality limits their use. Interest in vitamin D as a medical therapy has led to many trials; however, results using daily oral doses of vitamin D have been inconsistent. In the past 5 years, studies on the effect of bolus doses of vitamin D have produced surprising results. Bolus doses of vitamin D, given annually (at a dose of 300,000 IU or 500,000 IU) or monthly (at a dose of 24,000 IU or 60,000 IU) - equivalent to approximate daily doses of 800 IU, 1400 IU and 2,000 IU - result in a significant increase in the number of falls and fractures associated with serum levels of 25-hydroxyvitamin D greater than 40-45 ng/ml (equivalent to 100-112 nmol/l). These unexpected results show increased falls and fractures are adverse events related to vitamin D administration. Until further safety data is available, bolus dosing or daily doses should not exceed 3,000 IU and serum levels of 25-hydroxyvitamin D should not exceed 40-45 ng/ml (equivalent to 100-112 nmol/l) in elderly individuals.

The conundrum of whole foods versus macronutrient composition in assessing effects on insulin sensitivity.
            (Garvey, 2015) Download
In this issue of the Journal, Turner et al. (6) compared the relative ability of diets enriched in red meat, dairy products, or white meat (referred to as the control group) to affect insulin sensitivity in 47 overweight/obese middle-aged men and women. the differences in insulin sensitivity were quite small, necessitating the need for cautious interpretation of the data. Moreover, the authors emphasized different foods as sources of protein, but it may be differences in fat content and quality of fat in the foods that explain the data. In their Table 4, it is clear that the dairy product diet is characterized by higher total and saturated fat content and, by subtraction, lower amounts of poly- and monounsaturated fats.

Dietary modulation of the human colonic microbiota: updating the concept of prebiotics.
            (Gibson et al., 2004) Download
Prebiotics are non-digestible (by the host) food ingredients that have a beneficial effect through their selective metabolism in the intestinal tract. Key to this is the specificity of microbial changes. The present paper reviews the concept in terms of three criteria: (a) resistance to gastric acidity, hydrolysis by mammalian enzymes and gastrointestinal absorption; (b) fermentation by intestinal microflora; (c) selective stimulation of the growth and/or activity of intestinal bacteria associated with health and wellbeing. The conclusion is that prebiotics that currently fulfil these three criteria are fructo-oligosaccharides, galacto-oligosaccharides and lactulose, although promise does exist with several other dietary carbohydrates. Given the range of food vehicles that may be fortified by prebiotics, their ability to confer positive microflora changes and the health aspects that may accrue, it is important that robust technologies to assay functionality are used. This would include a molecular-based approach to determine flora changes. The future use of prebiotics may allow species-level changes in the microbiota, an extrapolation into genera other than the bifidobacteria and lactobacilli, and allow preferential use in disease-prone areas of the body.

Too much or too little? A review of the conundrum of selenium.
            (Gore et al., 2010) Download
Chemical elements such as selenium, fluoride, iron, calcium and magnesium are essential to the human being, although some are toxic when absorbed in high doses. In this paper, the risks associated with insufficient and excessive intake of selenium in the diet are reviewed, focusing on drinking water. Two different approaches are used to derive recommended nutrient intakes (RNI) for adequate nutritional status and guideline values to prevent excessive exposure. The former is based on the daily intake which meets the nutrient requirements of 97.5% of the population. The latter is a value derivation based on an assumed daily per capita consumption at the individual level, a conservative approach used where there is any uncertainty and is related to a negligible risk to health at population level across life stages. There is an increasing need to develop a conceptual framework bringing together aspects of toxicity and essentiality especially for elements apparently exhibiting narrow or overlapping ranges between essentiality and toxicity and to provide guidance on the nature and severity of risks in order to better protect human. While there are a number of frameworks available, these generally only consider food. There is a need to include water, which can be a significant source in some circumstances.

Global Non-Communicable Diseases-The Nutrition Conundrum.
            (Khandelwal et al., 2018) Download
The purpose of this piece is to try and unpack some of the methodological challenges and obstacles that give rise to the confusion and contradictions in the evolving field of nutrition epidemiology.

The carotenoid conundrum: improved nutrition boosts plasma carotenoid levels but not immune benefits of carotenoid supplementation.
            (Peters et al., 2011) Download
Carotenoids are widely heralded as central to honest signaling due to their dual roles as pigments and antioxidants/immunostimulants. The aim of this study is to test if diet quality and carotenoids alone or in an interaction influence condition, carotenoid availability in plasma and immune responsiveness. Therefore, a diet experiment during the moult of great tits, Parus major, was performed. In a two-way design, we manipulated general quality (digestibility, protein and vitamin content) as well as carotenoid (lutein) content of semi-synthetic diets. Higher quality diet improved individual condition since birds had greater body mass, and to a lesser extent, higher hematocrit. In addition to the expected positive effect of carotenoid supplementation and individual lutein consumption on circulating lutein, there was a positive effect of enhanced diet quality on plasma carotenoid levels. Carotenoid supplementation, but not diet quality, improved the local inflammatory response and maintenance of body mass during a humoral immune reaction. The enhancement of circulating carotenoid levels by improved general quality of the diet or individual condition could provide a testable, mechanistic explanation for the variation in effects of carotenoid supplementation studies.

Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum.
            (Raux et al., 2000) Download
The biosynthesis of cobalamin (vitamin B12) is described, revealing how the concerted action of around 30 enzyme-mediated steps results in the synthesis of one of Nature's most structurally complex 'small molecules'. The plethora of genome sequences has meant that bacteria capable of cobalamin synthesis can be easily identified and their biosynthetic genes compared. Whereas only a few years ago cobalamin synthesis was thought to occur by one of two routes, there are apparently a number of variations on these two pathways, where the major differences seem to be concerned with the process of ring contraction. A comparison of what is currently known about these pathways is presented. Finally, the process of cobalt chelation is discussed and the structure/function of the cobalt chelatase associated with the oxygen-independent pathway (CbiK) is described.

The antioxidant conundrum in cancer.
            (Seifried et al., 2003) Download
The health-related effects of interactions between reactive oxygen species (ROS) and dietary antioxidants and the consequences of dietary antioxidant supplementation on human health are by no means clear. Although ROS, normal byproducts of aerobic metabolism, are essential for various defense mechanisms in most cells, they can also cause oxidative damage to DNA, proteins, and lipids, resulting in enhanced disease risk. Dietary antioxidants (e.g., vitamin E, vitamin C, beta-carotene, and selenium), as well as endogenous antioxidant mechanisms, can help maintain an appropriate balance between the desirable and undesirable cellular effects of ROS. However, any health-related effects of interactions between dietary antioxidants and ROS likely depend on the health status of an individual and may also be influenced by genetic susceptibilities. Clinical studies of antioxidant supplementation and changes in either oxidative status, disease risk, or disease outcome have been carried out in healthy individuals, populations at risk for certain diseases, and patients undergoing disease therapy. The use of antioxidants during cancer therapy is currently a topic of heated debate because of an overall lack of clear research findings. Some data suggest antioxidants can ameliorate toxic side effects of therapy without affecting treatment efficacy, whereas other data suggest antioxidants interfere with radiotherapy or chemotherapy. Overall, examination of the evidence related to potential interactions between ROS and dietary antioxidants and effects on human health indicates that consuming dietary antioxidant supplements has pros and cons for any population and raises numerous questions, issues, and challenges that make this topic a fertile field for future research. Overall, current knowledge makes it premature to generalize and make specific recommendations about antioxidant usage for those at high risk for cancer or undergoing treatment.

Celebrating the 350th Anniversary of Phosphorus Discovery: A Conundrum of Deficiency and Excess.
            (Sharpley et al., 2018) Download
2019 will be the 350th anniversary of the discovery of phosphorus (P) by the alchemist Henning Brandt. This perspective traces the historical threads that P has weaved through the fabric of our society and identifies challenges to improve P stewardship in the future and for our future. A century after Brandt's discovery, P was identified in bone ash, which became the primary source of P until guano and ultimately rock P was mined to provide the various mineral formulations used today. Owing to limited supplies, a strategic shift in resource management ethics-from exploiting to conserving P resources-is needed. In agriculture, remedial strategies should consider when conservation practices can transition from P sinks to sources; however, a broader, long-term strategy for P stewardship is needed. This must include educing P loss in food and other wastes, ecovering P from waste streams, eusing P generated beneficial by-products, and estructuring production systems. A key action to enact such changes will be collaboration across all sectors of society and the supply chain, from field to fork and beyond. As this will likely increase the cost of food, fiber, and feed production, it will require an innovative mix of public and private initiatives.

Vitamin D insufficiency/deficiency - a conundrum.
            (Slovis and Chapman, 2008) Download
Keller and Barnes point out, the actual vitamin D level in children throughout the world is both a nutritional and a cultural problem. However, Keller and Barnes do not stop at informing us about this deficiency but go on to postulate that the lack of vitamin D in some children is responsible for skeletal lesions that are characteristic of child abuse. Have Keller and Barnes taken two separate entities and tried to connect them? Are they related, or is there another answer?


 

Introduction: the selenium conundrum.
            (Stapleton, 2000) Download
Selenium was first suspected of being an essential dietary trace element in the 1950s. We now know that indeed it is an essential biological element that serves as an integral component of several enzymes, including those in the families of deiodinases and glutathione peroxidases as well as selenoproteins P and W. The multi-author review that follows this introduction concentrates on the important biological role of selenium in enzymes as well as some of the physiological aspects of selenium as either a potential anticarcinogenic agent or insulin mimetic. What should become clear from these contributed articles is the complex and dynamic role that selenium plays in many biological processes and that the investigations in these areas are at the edge of exciting new frontiers.

The prebiotic concept and human health: a changing landscape with riboflavin as a novel prebiotic candidate
            (Steinert et al., 2016) Download
Emerging evidence suggests that the gut microbiota has a critical role in both the maintenance of human health and the pathogenesis of many diseases. Modifying the colonic microbiota using functional foods has attracted significant research effort and product development. The pioneering concept of prebiotics, as introduced by Gibson and Roberfroid in the 1990s, emphasized the importance of diet in the modulation of the gut microbiota and its relationships to human health. Increasing knowledge of the intestinal microbiota now suggests a more comprehensive definition. This paper briefly reviews the basics of the prebiotic concept with a discussion of recent attempts to refine the concept to open the door for novel prebiotic food ingredients, such as polyphenols, minerals and vitamins.

The vitamin D and cancer conundrum: aiming at a moving target.
            (Toner et al., 2010) Download
The case for the influence of vitamin D on health, including cancer prevention, is increasingly compelling. While some are calling for increases in the Tolerable Upper Intake Level, fortification, and dietary supplementation, questions regarding dose and individual response variability continue to merit attention. Colorectal cancer risk reduction with adequate vitamin D status is well documented. Protection has also been observed for cancer at all sites, skin, prostate, and breast. At the same time, some individuals may be adversely affected by elevated 25(OH)D concentrations with respect to risk of cancers of the prostate, breast, pancreas, and esophagus, and in some cases a U- or J-shaped association has been suggested. Future research should seek to clarify if and for whom there may be an increased risk for cancer at particular sites with high 25(OH)D concentrations, and the concentrations at which risk increases. Fundamentally, prospective longitudinal studies of these relationships are warranted. The health status, life stage, adiposity, estrogen exposure, and nutritional status of study participants should be taken into account. Continued investigation is necessary to ensure that vitamin D recommendations are appropriately targeted to individuals who stand to benefit most, while protecting vulnerable subgroups from risk of overexposure.

 


References

Arasaradnam, RP (2010), ‘The conundrum of folate and colorectal cancer (CRC) risk.’, Eur J Clin Nutr, 64 (12), 1501; author reply 1502. PubMed: 20877391
Baumann, U and J Juttner (2002), ‘Plant thioredoxins: the multiplicity conundrum.’, Cell Mol Life Sci, 59 (6), 1042-57. PubMed: 12169016
Baxter, P (2003), ‘Pyridoxine-dependent seizures: a clinical and biochemical conundrum.’, Biochim Biophys Acta, 1647 (1-2), 36-41. PubMed: 12686105
Boysen, G (2017), ‘The Glutathione Conundrum: Stoichiometric Disconnect between Its Formation and Oxidative Stress.’, Chem Res Toxicol, 30 (5), 1113-16. PubMed: 28426193
Chen, F, et al. (2016), ‘Could the gut microbiota reconcile the oral bioavailability conundrum of traditional herbs’, J Ethnopharmacol, 179 253-64. PubMed: 26723469
Danbolt, NC, DN Furness, and Y Zhou (2016), ‘Neuronal vs glial glutamate uptake: Resolving the conundrum.’, Neurochem Int, 98 29-45. PubMed: 27235987
Davey, RX (2017), ‘Vitamin D-binding protein as it is understood in 2016: is it a critical key with which to help to solve the calcitriol conundrum’, Ann Clin Biochem, 54 (2), 199-208. PubMed: 27742848
Evatt, ML (2014), ‘Parkinson disease: Low vitamin D and Parkinson disease--a causal conundrum.’, Nat Rev Neurol, 10 (1), 8-9. PubMed: 24296656
Fung, QM and A Szilagyi (2012), ‘Carbohydrate Elimination or Adaptation Diet for Symptoms of Intestinal Discomfort in IBD: Rationales for “Gibsons’ Conundrum”.’, Int J Inflam, 2012 493717. PubMed: 22518336
Gallagher, JC (2016), ‘Vitamin D and falls - the dosage conundrum.’, Nat Rev Endocrinol, 12 (11), 680-84. PubMed: 27494391
Garvey, WT (2015), ‘The conundrum of whole foods versus macronutrient composition in assessing effects on insulin sensitivity.’, Am J Clin Nutr, 101 (6), 1109-10. PubMed: 25971718
Gibson, GR, et al. (2004), ‘Dietary modulation of the human colonic microbiota: updating the concept of prebiotics.’, Nutr Res Rev, 17 (2), 259-75. PubMed: 19079930
Gore, F, J Fawell, and J Bartram (2010), ‘Too much or too little? A review of the conundrum of selenium.’, J Water Health, 8 (3), 405-16. PubMed: 20375470
Khandelwal, S, A Kurpad, and KMV Narayan (2018), ‘Global Non-Communicable Diseases-The Nutrition Conundrum.’, Front Public Health, 6 9. PubMed: 29435443
Peters, A, S Magdeburg, and K Delhey (2011), ‘The carotenoid conundrum: improved nutrition boosts plasma carotenoid levels but not immune benefits of carotenoid supplementation.’, Oecologia, 166 (1), 35-43. PubMed: 21301878
Raux, E, HL Schubert, and MJ Warren (2000), ‘Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum.’, Cell Mol Life Sci, 57 (13-14), 1880-93. PubMed: 11215515
Seifried, HE, et al. (2003), ‘The antioxidant conundrum in cancer.’, Cancer Res, 63 (15), 4295-98. PubMed: 12907593
Sharpley, A, et al. (2018), ‘Celebrating the 350th Anniversary of Phosphorus Discovery: A Conundrum of Deficiency and Excess.’, J Environ Qual, 47 (4), 774-77. PubMed: 30025053
Slovis, TL and S Chapman (2008), ‘Vitamin D insufficiency/deficiency - a conundrum.’, Pediatr Radiol, 38 (11), 1153. PubMed: 18810401
Stapleton, SR (2000), ‘Introduction: the selenium conundrum.’, Cell Mol Life Sci, 57 (13-14), 1823-24. PubMed: 11215508
Steinert, RE, et al. (2016), ‘The prebiotic concept and human health: a changing landscape with riboflavin as a novel prebiotic candidate’, Eur J Clin Nutr, 70 (12), 1348-53. PubMed: 27380884
Toner, CD, CD Davis, and JA Milner (2010), ‘The vitamin D and cancer conundrum: aiming at a moving target.’, J Am Diet Assoc, 110 (10), 1492-500. PubMed: 20869488