Translational Research – translating research into patient care strategies

“The answer is 17 years, what is the question: understanding time lags in translational research” – Morris, et al, 2011 (1)

It takes far too long for research findings to be ‘translated’ into health messages or techniques that reach the patient in need of health care guidance – 17 years on average according to the review of research study by Morris et al (2011). The team’s conclusion is that translational research is in need of further study but with more well defined terms and types of measurements so research by different teams can be compared. Twenty three studies were reviewed but the research parameters were diverse and not readily comparable. (1)

As a person with training and experience as a health care professional I followed general recommendations for general health and weight loss for many years but they didn’t help and I kept getting more sick with problems that didn’t show up on lab tests. Being told regularly that my symptoms must therefore be psychosomatic (mentally based) and that I should see a talk therapist did lead me to spending time with talk therapists and it helped somewhat but I kept getting more sick.

I knew I was physically sick, not just mentally making myself sick from stress or anxiety because I wasn’t always stressed or anxious and had always had some minor but chronic health problems as a child. So I eventually gave up on the standard not-helping-much answers and instead paid closer attention to my daily routine and dietary choices and slowly stopped doing any of the things that seemed to make me feel worse the next day. With the pay attention method I got somewhat better. Fibromyalgia and chronic fatigue symptoms were improved. Iodine supplements helped me with weight loss and a low dose antibiotic protocol developed for an autoimmune type of condition helped relieve my severe migraine problem.

Prescriptions can be quick and easy answers but they don’t always work, sometimes makes things worse, can delay trying other strategies that might work better – and can be expensive in insurance co-pays or be an out of pocket self pay expense. Health needs adequate sleep, with black out curtains and no lights, not even a digital alarm clock – keep it in a bedside table drawer or cover it with a towel. Even a little light at night can interfere with our production of melatonin and it helps with a variety of health needs throughout the body.

Health requires regular stretching and exercise that works out the heart and lungs and builds the other muscles somewhat. To maintain bone density requires weight bearing exercise – lifting weights in a warehouse or digging in a garden or in a gymnasium. Having the freedom to read text documents on your laptop while standing and using hand weights can multitask physical fitness needs with work or school needs. Varying positions and going for short walks occasionally is healthier than any type of job that requires too much of the same motions or having to stay in the same position for long periods of time.

Standing desks that can easily transition to a sitting desk can be as simple as a couple boxes under your laptop. Standing can allow some leg and arm stretches and then the boxes can be removed for some time spent sitting to type more intensively. Eight full hours in either position might be more of a health risk than being able to switch between the two options. (2)

Health requires all of the nutrients and additional fiber and antioxidants and other phytonutrients that aren’t considered essential in the same way vitamins are but may be necessary for more optimal health.

If it is reasonable to want to prevent measles or chickenpox, or other infectious diseases, then it seems reasonable to want to prevent age related degenerative disease by providing the body more of what it needs to remove toxins and rebuild tissue as it wears out. Even brain cells are replaced with new ones  – our entire body is not the same body that we had as a newborn. We are regularly removing old cells and growing new ones.

All truths are easy to understand once they are discovered. The point is to discover them. ~ Galileo

And the point of translational research is to improve the process of translating research findings into effective strategies for patient care. If research is still in early stages it may not be safe for all patients, finding out how to identify which patients it might help would then be a necessary step before translating the findings into patient education messages or health care protocols. How to guides ideally will always include safety warnings about which patients the health messages might harm if they were to use or be ineffective for their use.

As an individual it is good to know your rights as a patient and to seek health care professionals that take the time to listen. As a patient seeking a second opinion may be helpful and it can be helpful to write down your symptoms and mood changes, your daily diet or sleep habits, and any other routine habits in order to look back occasionally to see if any patterns show up in what is helping or not helping you feel better. We all need to remember that we are the ones living our lives and that makes us the ones in charge of taking care of our own health as best as we can.

It can take three weeks or more to build a habit and that suggests the reverse is likely true – and keeping a written tally sheet about the habit you want to change can help stay on track and help show where you may be veering off track. For more guidance, see Changing Habits, The Learning Center, University of North Carolina. (3)

Your Health Insurance agent is not your mother (probably), and in the current system large bills can lead to more profit for health insurance companies – so watch out for your  own budget by taking care of exercise, diet, and sleep habits and send your Health Insurance agent a nice card at the holidays instead of having them on speed dial for questions about your enormous co-pays. Insurance is nice but 10 or 20% of an enormous bill is still more than most of us have in the bank or can easily borrow. (4)

Bankruptcy due to health care costs has become too common – stay out of bankruptcy court by spending more time on daily health care habits – the research is fairly conclusive regarding the basics –

  • ideally at least 30-60 minutes of exercise 3-5 times per week,
  • drink plenty of water for thirst
  • and eat 5-9 servings of vegetables/whole fruit per day, get adequate protein, whole grains and essential omega 3 fatty acids without too much saturated and trans fats each day. Trying to include a serving of fatty fish three times per week can be a source of omega 3 fatty acids or vegetarian sources include walnuts, hemp seed kernels or ground flax seeds. Including a serving of beans, nuts and seeds on most days may increase the amount of magnesium and other important trace nutrients in the daily/weekly diet.
  • Six hours of sleep seems to be a minimum need for most people and more than eight hours on a regular basis may be too much or a sign of health or depression problems in adults once they are out of the teen years, (teens may benefit from ten hours of sleep per day, (6)). Short naps during the day can be a healthful activity and may increase work productivity, 20-30 minutes may be ideal. Longer naps may lead to waking up groggy instead of refreshed. (5)
  • Social activity and other relaxing hobbies also seem to be helpful for health.

/Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes. Thanks./

  1. Zoë Slote Morris, Steven Wooding, and Jonathan Grant,

    The answer is 17 years, what is the question: understanding time lags in translational research., J R Soc Med. 2011 Dec; 104(12): 510–520. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241518/

  2. Robert H. Shmerling, MD, The Truth Behind Standing Desks, Sept. 23, 2016, Harvard Health Blog, Harvard Health Publishing, health.harvard.edu,  https://www.health.harvard.edu/blog/the-truth-behind-standing-desks-2016092310264?utm_campaign=shareaholic&utm_medium=twitter&utm_source=socialnetwork
  3. Changing Habits, The Learning Center, University of North Carolina, https://learningcenter.unc.edu/tips-and-tools/changing-habits/
  4. Why Your Health Insurer Doesn’t Care About Your Big Bills, propublica.org, https://www.propublica.org/article/why-your-health-insurer-does-not-care-about-your-big-bills
  5. Napping, sleepfoundation.org, https://sleepfoundation.org/sleep-topics/napping
  6. See Chapter Two: The Lost Hour, Po Bronson and Ashley Merryman, NurtureShock: New Thinking About Children, Twelve, Hatchette Book Group, New York, 2009 http://www.nurtureshock.com/

Additional references for more information on translational medicine:

Excerpt from a post about my own genetic screening (Genetic Screening can give guidance about potential medication adverse reactions, 2018):

Additional reference for further discussion of the advances in the use of genetic screenings for medication risk is available in a book that is already slightly dated with the rapid advances in technology but as a starting point it is helpful for an overview on the history of technological advances in the area of medical care: The Creative Destruction of Medicine: How the Digital Revolution will Create Better Health Care, by Eric Topol, M.D., 2013. Basic Books. ISBN: 978-0465061839. (1) (“Book Review…,” and summary, by Jung A Kim, RN, PhD, PubMed_2)

One of the pioneers in personal genetic screening was Esther Dyson, a venture capitalist. She quoted a colleague regarding why she agreed to be one of the first ten participants in the Personal Genome Project:

“You would no more take a drug without knowing the relevant data from your genome than you would get a blood transfusion without knowing your blood type.” [128] (1)

The future of individualized health care will include genetic screening for everyone and what isn’t addressed in the book by cardiologist and translational research specialist Eric Topol, M.D. is the use of genetic screening for individualized nutrition guidance. In addition to discovering what medications may work better or be more dangerous for an individual genetic screening can target which types of exercise or diet plans may be more or less beneficial and which nutrients may need to be restricted or supplemented more than the average guidance.

My previous genetic screening was for fewer genes but which were chosen as most commonly a problem for children on the autism spectrum – I had 11 of the 30 and the guidance led to supplements and diet changes that have helped me feel better and have better mood stability – Methylation Cycle Defects – in me, Genetic Screening “For Research Purposes Only” – at this stage “For Research Purposes Only” is a legal phrase as genetic screening is not considered consistent enough for use as a diagnostic tool, but my personal health is of significant interest to me.

  1. Eric Topol, M.D,, The Creative Destruction of Medicine: How the Digital Revolution will Create Better Health Care, 2013. Basic Books. ISBN: 978-0465061839.  (1) Chapter 5, Biology: Sequencing the Genome, page 117: [128]
  2. Jung A Kim, RN, PhD, Book Review: The Creative Destruction of Medicine: How the Digital Revolution will Create Better Health CareHealth Inform Res. 2013 Sep; 19(3): 229–231.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810531/ PubMed_2)

[128] Esther Dyson, “Full Disclosure,” Wall Street Journal, July 25, 2007, A15.

Glutathione, Nrf2, Autism and glyphosate

Glyphosate use has escalated (1) at a similar rate and overlapping time frame to the increase in autism in children. The rate of autism in Japanese children is even greater than in U.S. children. The Japanese children may be consuming a larger percent of GMO soy from the U.S. as the country is a significant importer of the crop. (4)Testing has shown that basically all GMO soy, Roundup Ready, has residue of glyphosate. (1) Glyphosate residue has been found in all foods tested by the FDA except for broccoli. (6)

The herbicide Roundup has been shown to induce oxidative stress in animal studies (5), and children with autism have been shown to have an increase in oxidative stress and reduced levels of an antioxidant, glutathione, (2), that is made within our bodies during normal health.

Use of Nrf2 promoting foods might help increase our own production of glutathione. (3) Broccoli is one food that may help promote our own supply of Nrf2 which then helps us make the antioxidant glutathione.

Glyphosate may be metabolized into other chemicals within the body and it or the metabolites may inhibit enzymes important for a variety of functions throughout the body. (7) Radioactive labeling of glyphosate in animal studies by the company Monsanto showed that bioaccumulation of the chemical does occur, particularly in blood cells found in bone and bone marrow, also in the testes and ovaries, see slide 11 for a copy of the table of data: (8).

A thorough overview of the theoretical and known health risks of glyphosate is available by a personal fitness coach from Australia, Alex Fergus, (9), in part two of a three part series on his website. Part one covers the history of the synthetic chemical’s discovery and patent history and increased agricultural use in the U.S. and globally, (10), and his list of tips on how to protect yourself and try to reduce exposures through diet and supplements, (11). The list is comprehensive however doesn’t include Epsom salt/magnesium sulfate as an additional source of bioactive sulfate. Baths or footsoaks provide a topical absorption route that would bypass any problems with malabsorption in the digestive system or problems with sun exposure to bioactivate other forms of sulfur into the bioactive sulfate form.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

  1. John Peterson Myers, Michael N. Antoniou, Bruce Blumberg, Lynn Carroll, Theo Colborn, Lorne G. Everett,Michael Hansen, Philip J. Landrigan, Bruce P. Lanphear, Robin Mesnage, Laura N. Vandenberg, Frederick S. vom Saal,Wade V. Welshons, and Charles M. Benbrook,

    Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement.  Environ Health. 2016; 15: 19. Pub. online 2016 Feb 17,  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756530/?utm_content=buffere016d&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer

  2. S. Rose, S MelnykO PavlivS BaiT G NickR E Frye,  S J James, Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain, Translational Psychiatry Vol. 2, page 134 (2012), nature.com, https://www.nature.com/articles/tp201261
  3. Megan L. Steele, Stacey Fuller, Mili Patel, Cindy Kersaitis, Lezanne Ooi, and Gerald Münch, Effect of Nrf2 activators on release of glutathione, cysteinylglycine and homocysteine by human U373 astroglial cellsRedox Biol. 2013; 1(1): 441–445. Published online 2013 Sep 12, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814960/

  4. Zen Honeycutt, Shockingly Higher Rates of Autism and Developmental Delays in Asia, Report from Japan speaking tour, March 1-10, March 21, 2017, MomsAcrossAmerica.com, https://www.momsacrossamerica.com/shockingly_higher_rates_of_autism_and_developmental_delays_in_asia
  5.  Low toxic herbicide Roundup induces mild oxidative stress in goldfish tissuesChemosphere, Vol. 76, Issue 7, Aug 2009, pp 932-937
    ScienceDirect,  https://www.sciencedirect.com/science/article/pii/S0045653509005256
  6. Toxic Weed Killer Glyphosate Found in Most Foods Sold in the U.S., wakeup-world.com, https://wakeup-world.com/2018/05/24/toxic-weed-killer-glyphosate-found-in-most-foods-sold-in-the-u-s/
  7. Ford et al., Mapping Proteome-wide Targets of Glyphosate in Mice, Cell Chemical Biology (2016), http://dx.doi.org/10.1016/
    j.chembiol.2016.12.013 https://www.cell.com/cell-chemical-biology/pdf/S2451-9456(16)30474-3.pdf
  8. Anthony Samsel, Glyphosate Herbicide Pathways To Modern Diseases Synthetic Amino Acid And Analogue of Glycine Mis-incorporation Into Diverse Proteins , Slides 2016,,   https://people.csail.mit.edu/seneff/DC2016/AnthonySamsel_DC2016.pdf (8)
  9. Alex Fergus, Glyphosate: Why You Need to Eat Organic,   https://www.alexfergus.com/blog/glyphosate-why-you-need-to-eat-organic (9)
  10. Alex Fergus, Glyphosate: The Weed Killer Found in Our Food & Water, https://www.alexfergus.com/blog/glyphosate-the-weed-killer-found-in-our-food-water (10)
  11. Alex Fergus, How to Protect Yourself from Glyphosate, https://www.alexfergus.com/blog/how-to-protect-yourself-from-glyphosate (11)

Choline and betaine – water soluble nutrients

Choline is a newer discovery in the nutrient world. It is considered to be a member of the water soluble B vitamins group which are nutrients involved in metabolism – the use of energy within the body. We can produce small amounts of choline so it isn’t considered a vitamin but as we can not produce enough for health it is considered an essential nutrient. (1) Betaine is a slightly different form of choline. Choline is found throughout the body but is particularly important within the brain and is needed for the neurotransmitter acetylcholine. Betaine is a metabolite of choline.

Choline, a water soluble nutrient. Foods Sources and symptoms of deficiency.

Choline is most typically found within phospholipids (such as phosphatidylcholine) which are important in membranes and as messenger chemicals within the brain and in the immune system. It may play a role in prenatal brain development but research on supplementation within pregnancy r to protect cognitive skills in the elderly is still in early stages. (1)

Choline is a  methyl donor (1) which means it can share a methyl group – essentially one carbon atom with three hydrogen atoms with an overall neutral charge.

An important role of methyl groups is in the release of energy from sugar within mitochondria. The methyl group is passed back and forth between nutrients and enzymes that are involved in breaking down a molecule of fat or sugar for use of the stored energy that is released when a double bond is broken. The methyl group is combined with an acetyl group when it is removed from the area on the chain of carbon molecules when a double bond is broken. An acetyl group is an atom of carbon combined with one atom of hydrogen and the group has a negative charge. The process for breaking down the glucose sugar molecule is called the Krebs cycle and most beginning level organic chemistry or nutrition students will remember having to memorize all of the steps involved. My summary may be inaccurate – college was a long time ago – the important point is that B vitamins and methyl donors are needed for mitochondria to be able to release energy from glucose/sugar molecules).

  • (The Krebs cycle is also known as the “citric acid cycle or the tricarboxylic acid (TCAcycle.” More info: Krebs cycle.)

Methyl groups are also important in controlling gene activity. They act like an on/off switch for genes. A gene that is fully methylated – all the available double bonds between carbon atoms are broken into single bonds with a methyl group added instead – is in the off position, the protein that the gene would encode is not being made. Genes that are unmethylated have double bonds and are in the on position, the pattern for assembling amino acids into a protein can be read by a matching strand of RNA and the protein can be formed (generally in the endoplasmic reticulum or Golgi apparatus areas of a cell).

Betaine and the more familiar B vitamins folate (B9 if anyone is counting), B6 and B12 are also methyl donors. Folate deficiency has been associated with less gene methylation (a histone is part of a gene). (2) More about methyl donors as a group is available here:  Methyl Donors and BPA.

  • The number system for naming B vitamins was derived at an earlier stage of research and some of the chemicals that were given numbers at the time were discovered to not be essential nutrients – meaning the body was able to form them within the normal health and didn’t essentially need to have them included in the diet (so that is why we don’t hear about a B4, B8, B10 or B11).

Excessive intake of choline above 7500 milligrams may cause a drop in blood pressure, sweating, vomiting and digestive upset, and change in body odor. The recommended Upper Limit is 3,500 mg/day. It would be difficult to reach that amount with food sources. (Safety information, lpi.oregonstate.edu)

Food Sources of Choline:

Good sources of choline include meats, fish & shellfish, eggs/egg yolks, cheese, milk, yogurt, broccoli, cauliflower, cabbage, kale, kohlrabi and other cruciferous vegetables, green leafy vegetables, pomegranate seeds, sesame seeds, tahini, peanuts,  soybeans, beans, brown rice, whole grains.

Food Sources of Betaine:

Sweet potatoes, meats, cheese, beets, basil, spinach, green leafy vegetables, brown rice, whole grains.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

References:

  1. Choline, Linus Pauling Institute, Oregon State University, http://lpi.oregonstate.edu/mic/other-nutrients/choline
  2. Benjamin A. Garcia, Zigmund Luka, Lioudmila V. Loukachevitch, Natarajan V. Bhanu, Conrad Wagner, Folate deficiency affects histone methylation,

    Medical Hypotheses, Volume 88, March 2016, Pages 63-67, ScienceDirect, https://www.sciencedirect.com/science/article/pii/S0306987716000116

  3. Foods used in the 30% Calories from Carbohydrates Menu Plans, https://effectiveselfcare.info/2018/05/19/healthy-hair-is-the-proof-of-a-healing-diet/

Pantothenic Acid – vitamin B5

Vitamin B5 is typically referred to by its chemical name Pantothenic Acid. Why some of the B Vitamins are called a name and some by the number may have to do with the variety of the forms commonly found in the body or in the food supply. Vitamin B6 has several important chemical forms as do vitamin D and vitamin E. Getting a variety of foods within the diet on a regular, daily, weekly or even monthly basis can help to provide some of the various forms. Vitamin E in a supplement might only provide one of the bioactive forms of the group of nutrients while eating nuts and seeds would be providing some of all of the group in addition to B vitamins and other minerals.

Pantothenic Acid – vitamin B5. Food Sources and Symptoms of Deficiency.

Pantothenic Acid is a water soluble B vitamin that is essential in metabolic pathways in all forms of life, plants, animals and microbes. It is a precursor chemical for coenzyme A which is involved in many reactions that help sustain life and is needed for other proteins that are needed for making fatty acids – fats of different lengths and types. It does have other active chemical forms but is not typically referred to by their names, pantothenol – may help with healing skin wounds, research is in early stages; and pantethine – may help lower cholesterol and lipid (fat) levels in the blood. (1)

Dietary deficiency of Pantothenic Acid is very rare as the vitamin is found in most animal and plant food products. There have been no known cases of overdose/toxicity so no Upper Limit for safety has been set. Deficiency is so rare it has only been documented in prisoners of war (POWs) and the symptoms relieved by supplementation of Pantothenic Acid were reported by the POWs to be “numbness and painful burning and tingling in their feet.” (1)

Pantothenic Acid is involved in converting the B vitamin folate into an active form so a deficiency in Pantothenic Acid might result in folate deficiency symptoms, (1) (megaloblastic anemia with fatigue and normal levels of iron but with fewer red blood cells that are immature, too large (macrocytic) and nonfunctional (2). Vitamin B12 deficiency can also be a cause with similar lab values but supplements or injections of that B vitamin wouldn’t help if deficiency of the active form of folate was the cause. Supplements of folic acid, the inactive form most commonly used in multi-vitamins or fortified foods, wouldn’t help either. Beans, peas and asparagus are good food sources of folate, more information about that B vitamin is available here: (Folate is essential and Folic Acid is commonly available)

Genetic differences may affect some individual’s ability to phosphorylate (add atoms of the mineral Phosphorus) to the molecule of Pantothenic Acid for the transformation of the vitamin precursor into the bioactive coenzyme A. The enzyme is needed for transporting fatty acids (lipids/fats) into the mitochondria for use for energy production. Someone with a genetic difference might not be able to use fats for energy as well as someone with typical ability to phosphorylate the Pantothenic Acid molecules in the production of Coenzyme A. One known gene that could inhibit the production of Coenzyme A is Pantothenic acid kinase II (PANK2) . Symptoms of people with a double gene difference in PANK2 may include changes in movement control (dystonia), and impaired vision, intelligence, speech, and behavior, and personality disorders (15). (1)

Symptoms of deficiency of Coenzyme A might include gaining weight more easily than average and more readily getting tired when exercising for longer amounts of time. That is my interpretation though.

I have a different genetic difference that affects phosphorylation so I may also have trouble producing Coenzyme A. Betaine-homocysteine methyltransferase (BHMTis a gene involved in protein metabolism that could cause reduced Dimethylglycine and methionine.  Chronic Fatigue Syndrome has been associated with a lack of Dimethylglycine (the amino acid – glycine). The metabolic pathways are very complex chemistry and it looks like this gene is more involved in the chemistry of the B vitamins choline and betaine. The phosphorylation problem is more specifically with phospholipids and  glycerophospholipids – both essential parts of membranes and cannabinoids. (Glycerophospholipid biosynthesis) (Phospholipid metabolism)

I will discuss betaine and choline in additional posts. An overview about phospholipids and food sources is available in the post Macro & micro-nutrients, an overview & food sources.

Symptoms of Pantothenic Acid deficiency in lab animals or other groups of animals found to have deficiency of vitamin B5 in their food supply included skin irritations, graying of fur or feather abnormalities, anemia due to reduced heme production,  nerve problems involving reduced myelin sheath, low blood glucose, rapid breathing and heart rate, and damaged adrenal glands. (1)

So it is good that Pantothenic Acid is readily available in many foods because clearly it is very important to our health. However supplements of Pantothenic Acid or rubbing it directly on the scalp or gray hair did not restore hair color in humans with gray hair. (1)

Food Sources for Pantothenic Acid (vitamin B5):

Organ meats (liver and kidney), Meats, Fish and Shellfish, Salmon, Egg yolk, MIlk, Yogurt, Cheese, Avocado, Broccoli Sweet Potato, Carrot, Celery, Mushrooms, Pomegranate Seeds, Sesame Seeds/Tahini, Beans, Nuts, Seeds, Almonds, Walnuts, Whole Grains, Brown Rice, Enriched Flour Products depending on the source – Canadian guidelines require it while the U.S guidelines do not.  (4, 5) “Processing and refining grains may result in a 35 to 75% loss. Freezing and canning of foods result in similar losses (16).” (1)

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

References:

  1. Pantothenic Acid, Linus Pauling Institute, Oregon State University, http://lpi.oregonstate.edu/mic/vitamins/pantothenic-acid
  2. Anemia of Folate Deficiency, https://www.hopkinsmedicine.org/healthlibrary/conditions/hematology_and_blood_disorders/anemia_of_folate_deficiency_85,P00089
  3. Foods used in the 30% Calories from Carbohydrates Menu Plans, https://effectiveselfcare.info/2018/05/19/healthy-hair-is-the-proof-of-a-healing-diet/
  4. Institute of Medicine (US) Committee on Use of Dietary Reference Intakes in Nutrition Labeling. Dietary Reference Intakes: Guiding Principles for Nutrition Labeling and Fortification. Washington (DC): National Academies Press (US); 2003. 3, Overview of Food Fortification in the United States and Canada. https://www.ncbi.nlm.nih.gov/books/NBK208880/
  5. Guidance Document Repository (GDR), Prohibition against the sale of unenriched white flour and products containing unenriched flour. Canadian Food Fortification Guidelines; Grain and Bakery Products,  Canadian Food Inspection Agency, http://www.inspection.gc.ca/food/labelling/food-labelling-for-industry/grain-and-bakery-products/unenriched-flour/eng/1415915977878/1415915979471

15. Kurian MA, Hayflick SJ. Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. Int Rev Neurobiol. 2013;110:49-71.  (https://www.ncbi.nlm.nih.gov/pubmed/24209433)

16. Food and Nutrition Board, Institute of Medicine. Pantothenic acid. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:357-373. National Academy Press,  (https://www.nap.edu/read/6015/chapter/12)