Arrieta, O., Gonzalez-De la Rosa CH, Arechaga-Ocampo, E., Villanueva-Rodriguez, G., Ceron-Lizarraga, T. L., Martinez-Barrera, L., Vazquez-Manriquez, M. E., Rios-Trejo, M. A., Alvarez-Avitia, M. A., Hernandez-Pedro, N., Rojas-Marin, C., and De la Garza, J. Randomized phase II trial of All-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer. J Clin Oncol. 7-20-2010;28(21):3463-3471. View abstract.
The dietary supplements industry in the United Kingdom (UK), one of the 28 countries in the bloc, strongly opposed the Directive. In addition, a large number of consumers throughout Europe, including over one million in the UK, and various doctors and scientists, had signed petitions by 2005 against what are viewed by the petitioners as unjustified restrictions of consumer choice.[101] In 2004, along with two British trade associations, the Alliance for Natural Health (ANH) had a legal challenge to the Food Supplements Directive[102] referred to the European Court of Justice by the High Court in London.[103]
Since vitamin A is fat-soluble, disposing of any excesses taken in through diet takes much longer than with water-soluble B vitamins and vitamin C. This allows for toxic levels of vitamin A to accumulate. These toxicities only occur with preformed (retinoid) vitamin A (such as from liver). The carotenoid forms (such as beta-carotene as found in carrots), give no such symptoms, but excessive dietary intake of beta-carotene can lead to carotenodermia, a harmless but cosmetically displeasing orange-yellow discoloration of the skin.[37][38][39]
^ Siscovick DS, Barringer TA, Fretts AM, Wu JH, Lichtenstein AH, Costello RB, Kris-Etherton PM, Jacobson TA, Engler MB, Alger HM, Appel LJ, Mozaffarian D (2017). "Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory From the American Heart Association". Circulation. 135 (15): e867–e884. doi:10.1161/CIR.0000000000000482. PMID 28289069.
Kennedy, K. A., Stoll, B. J., Ehrenkranz, R. A., Oh, W., Wright, L. L., Stevenson, D. K., Lemons, J. A., Sowell, A., Mele, L., Tyson, J. E., and Verter, J. Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low? The NICHD Neonatal Research Network. Early Hum Dev. 7-24-1997;49(1):19-31. View abstract.

Guenther, L., van de Kerkhof, P. C., Snellman, E., Kragballe, K., Chu, A. C., Tegner, E., Garcia-Diez, A., and Springborg, J. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol 2002;147(2):316-323. View abstract.
The RAR-RXR heterodimer recognizes retinoic acid response elements (RAREs) on the DNA whereas the RXR-RXR homodimer recognizes retinoid "X" response elements (RXREs) on the DNA; although several RAREs near target genes have been shown to control physiological processes,[21] this has not been demonstrated for RXREs. The heterodimers of RXR with nuclear receptors other than RAR (i.e. TR, VDR, PPAR, LXR) bind to various distinct response elements on the DNA to control processes not regulated by vitamin A.[16] Upon binding of retinoic acid to the RAR component of the RAR-RXR heterodimer, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery.[56] This response can upregulate (or downregulate) the expression of target genes, including Hox genes as well as the genes that encode for the receptors themselves (i.e. RAR-beta in mammals).[16]
Rejnmark, L., Avenell, A., Masud, T., Anderson, F., Meyer, H. E., Sanders, K. M., Salovaara, K., Cooper, C., Smith, H. E., Jacobs, E. T., Torgerson, D., Jackson, R. D., Manson, J. E., Brixen, K., Mosekilde, L., Robbins, J. A., Francis, R. M., and Abrahamsen, B. Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J Clin.Endocrinol.Metab 2012;97(8):2670-2681. View abstract.

Bhoopalam, N., Campbell, S. C., Moritz, T., Broderick, W. R., Iyer, P., Arcenas, A. G., Van Veldhuizen, P. J., Friedman, N., Reda, D., Warren, S., and Garewal, H. Intravenous zoledronic acid to prevent osteoporosis in a veteran population with multiple risk factors for bone loss on androgen deprivation therapy. J Urol. 2009;182(5):2257-2264. View abstract.
A dietary supplement is a manufactured product intended to supplement the diet when taken by mouth as a pill, capsule, tablet, or liquid.[2] A supplement can provide nutrients either extracted from food sources or synthetic, individually or in combination, in order to increase the quantity of their consumption. The class of nutrient compounds includes vitamins, minerals, fiber, fatty acids and amino acids. Dietary supplements can also contain substances that have not been confirmed as being essential to life, but are marketed as having a beneficial biological effect, such as plant pigments or polyphenols. Animals can also be a source of supplement ingredients, as for example collagen from chickens or fish. These are also sold individually and in combination, and may be combined with nutrient ingredients. In the United States and Canada, dietary supplements are considered a subset of foods, and are regulated accordingly. The European Commission has also established harmonized rules to help insure that food supplements are safe and properly labeled.[3]
Newton-Bishop, J. A., Beswick, S., Randerson-Moor, J., Chang, Y. M., Affleck, P., Elliott, F., Chan, M., Leake, S., Karpavicius, B., Haynes, S., Kukalizch, K., Whitaker, L., Jackson, S., Gerry, E., Nolan, C., Bertram, C., Marsden, J., Elder, D. E., Barrett, J. H., and Bishop, D. T. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. J Clin.Oncol. 11-10-2009;27(32):5439-5444. View abstract.
Improving public information about use of dietary supplements involves investments in professional training programs, further studies of population and nutrient needs, expanding the database information, enhancing collaborations between governments and universities, and translating dietary supplement research into useful information for consumers, health professionals, scientists, and policymakers.[134] Future demonstration of efficacy from use of dietary supplements requires high-quality clinical research using rigorously-qualified products and compliance with established guidelines for reporting of clinical trial results (e.g., CONSORT guidelines).[107]
Kobbe, R., Kreuzberg, C., Adjei, S., Thompson, B., Langefeld, I., Thompson, P. A., Abruquah, H. H., Kreuels, B., Ayim, M., Busch, W., Marks, F., Amoah, K., Opoku, E., Meyer, C. G., Adjei, O., and May, J. A randomized controlled trial of extended intermittent preventive antimalarial treatment in infants. Clin Infect.Dis 7-1-2007;45(1):16-25. View abstract.
Ramlau, R., Zatloukal, P., Jassem, J., Schwarzenberger, P., Orlov, S. V., Gottfried, M., Pereira, J. R., Temperley, G., Negro-Vilar, R., Rahal, S., Zhang, J. K., Negro-Vilar, A., and Dziewanowska, Z. E. Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin.Oncol. 4-10-2008;26(11):1886-1892. View abstract.
Ushiroyama, T., Ikeda, A., Sakai, M., Higashiyama, T., and Ueki, M. Effects of the combined use of calcitonin and 1 alpha-hydroxycholecalciferol on vertebral bone loss and bone turnover in women with postmenopausal osteopenia and osteoporosis: a prospective study of long-term and continuous administration with low dose calcitonin. Maturitas 12-14-2001;40(3):229-238. View abstract.
Vitamin D emerged as a protective factor in a prospective, cross-sectional study of 3,121 adults aged ≥50 years (96% men) who underwent a colonoscopy. The study found that 10% had at least one advanced cancerous lesion. Those with the highest vitamin D intakes (>645 IU/day) had a significantly lower risk of these lesions [55]. However, the Women's Health Initiative, in which 36,282 postmenopausal women of various races and ethnicities were randomly assigned to receive 400 IU vitamin D plus 1,000 mg calcium daily or a placebo, found no significant differences between the groups in the incidence of colorectal cancers over 7 years [56]. More recently, a clinical trial focused on bone health in 1,179 postmenopausal women residing in rural Nebraska found that subjects supplemented daily with calcium (1,400–1,500 mg) and vitamin D3 (1,100 IU) had a significantly lower incidence of cancer over 4 years compared with women taking a placebo [57]. The small number of cancers (50) precludes generalizing about a protective effect from either or both nutrients or for cancers at different sites. This caution is supported by an analysis of 16,618 participants in NHANES III (1988–1994), in which total cancer mortality was found to be unrelated to baseline vitamin D status [58]. However, colorectal cancer mortality was inversely related to serum 25(OH)D concentrations. A large observational study with participants from 10 western European countries also found a strong inverse association between prediagnostic 25(OH)D concentrations and risk of colorectal cancer [59].
In Europe are regulations that define limits of vitamin (and mineral) dosages for their safe use as dietary supplements. Most vitamins that are sold as dietary supplements are not supposed to exceed a maximum daily dosage referred to as the tolerable upper intake level (UL). Vitamin products above these regulatory limits are not considered supplements and should be registered as prescription or non-prescription (over-the-counter drugs) due to their potential side effects. The European Union, United States, Japan establish recommended upper intake levels.[8][33][34]
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