Schizophrenia Round-up and Back to School

Today I went back to school.  Every fall, I help teach the introduction to psychiatry class for the second year medical students at my institution.  I work with a small group, teaching basic interviewing and write-up skills.  Today was a large lecture, though, so I got to be in the audience, thumbing through this month's stack of journals while the students were Introduced to Psychiatry.  

There are a few interesting papers in the Archives of General Psychiatry this month, which isn't always the case.  The Archives tends to have really tedious genetic polymorphism and functional MRI studies out the wazoo.  You get paper headings like "Reduced brain white matter integrity in trichotillomania." Which, believe me, is not even as interesting as it sounds.  Still, the Archives is an excellent journal and they don't accept horrible studies, just boring ones.

The first interesting one is "Modification of Cognitive Performance in Schizophrenia by Complexin 2 Gene Polymorphisms." (I know, it sounds really boring!  But give it a chance.)  Turns out this group in Germany put together a database of genetic data for schizophrenia research.  23 different research centers compiled the genetic data of 1071 patients with schizophrenia and 1079 controls.  Then they threw the DNA into their big machines, and out pops loads of data.  Over 3000 phenotypic data points for each patient!  There's a specific gene, complexin 2, which codes for a type of protein that regulates how synaptic signaling happens in the brain.  Specifically, complexin 1 and 2 control the release of the soluble-N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE).  Differences in the complexin 2 proteins and mRNA have been noted in previous autopsy studies of schizophrenics, so the genes were an obvious place to look.  In those autopsy studies, a significant decrease in complexin 2 was found in regions of the brain that are specifically damaged in schizophrenia (like the dorsolateral prefrontal cortex and the hippocampus).  This same protein/gene expression was found to be decreased in studies of bipolar disorder, Alzheimer's, and Huntington's disease, but in different parts of the brain more affected by those other disorders.   All of the disorders, though , have symptoms of cognitive impairment, meaning in the advanced stages of each disease, you just can't think as clearly as you once did.  And, sure enough, when they traced the schizophrenia patients who had certain types of poorly expressed complexin 2 gene, they tended to have more cognitive impairment than the other schizophrenia patients

Okay, that's not particularly interesting, at least from an evolutionary medicine standpoint.  Except I couldn't help but notice all those disorders up there (except bipolar disorder) are ones I've discussed in the blog who have some evidence to link them to wheat or to metabolic syndrome.  Mice with knocked out complexin 2 genes have a few issues, but apparently not cognitive ones.  Until you take those mice and deprive them of their mothers.  Then the complexin 2 knockout mice get mouse dementia, of sorts.   It's the genetic difference plus the stress that seems to cause the disease.  Good old two-hit hypothesis.


Next up is one that will warm the cockles of your sun-worshiping hearts.   "Neonatal Vitamin D Status and Risk of Schizophrenia: A Population-Based Case Control Study."  Thank you, Netherlands, who apparently keeps dried blood samples from all the babies born there.  The researchers took 424 individuals with schizophrenia and 424 sex and age matched controls, and pulled their blood samples from the big bank 'o blood, and figured out each neonate's vitamin D levels.


Vitamin D is a big suspect in schizophrenia for the following reasons - Vitamin D undoubtedly plays a role in the development of the brain.  People born in winter and spring have higher risk for developing schizophrenia, and the farther you are born from the equator, the more likely your birth month will be a factor.  Immigrants with dark skin who move to northern countries also have children with higher rates of schizophrenia.  In addition, city kids are more likely to develop schizophrenia compared to country kids.   This study is the first time someone was able to go back and directly check the vitamin D levels from neonatal blood of people who later get schizophrenia.

The average level of vitamin D (measured as 25 (OH) vitamin D3) varied widely from winter to summer, with babies born in March (cases and controls) having the lowest levels, around 26 (deficient), and babies born in August having an average level of nearly 50 (which is good).  One caveat - the actual level may be misleading.  The level might degrade over time, and these samples were up to 27 years old when tested.  However, since there were matched controls of the same age for each patient, it was presumed that the degradation would be the same for both sets of data.     

But now the key results - babies born with a vitamin D level of 46.5 had the lowest risk for schizophrenia (again, that might not be the actual level, measured so many years later).  The babies within the lowest two quintiles (the lowest 40%) of vitamin D levels had significantly increased risk.  Surprisingly, babies in the highest quintile, with the highest vitamin D levels, had higher risk too.  The researchers were able to go back and check for all sorts of variables which might confound things - UV light therapy at birth for high bilirubin might affect vitamin D levels, for example, admission to the NICU, age, sex, etc. etc. and nothing seemed to change the overall U-shaped data curve, with the "sweet spot" between the 3rd and 4th quintiles of vitamin D levels.  Now the researchers wisely emphasized caution when considering these results - it's an observational study, and there can be plenty of confounders nobody thought of.  However, if the cause-effect relationship holds true, the researchers suggest that mere vitamin D supplementation in dark-skinned immigrants in northern countries could reduce the incidence of schizophrenia in those populations by "a staggering 87%."


A third study in this same issue is called "Birth Weight, Schizophrenia, and Adult Mental Disorder," where the researchers did pretty much what you might think, but on a very large scale.  They followed 1.49 million single babies born in Sweden and Denmark between 1973 and 1986.  Both countries have "comprehensive national registers of psychiatric treatment."  In 2002 (Sweden) and 2005 (Denmark), these countries had 5,445 registered cases of schizophrenia and 57,455 cases of "any adult psychiatric disorder."  (My first thought - 5445 cases of schizophrenia seems low out of 1.49 million, and it is only 0.37 %.  There should be around 14,900 cases as the worldwide prevalence is right around 1%.  Just something to keep in mind!) 


The results - birth weight of less than 2500 grams (5 pounds, 8 ounces) in these babies translated into a higher risk for schizophrenia, and the risk actually decreases (for schizophrenia) as the birth weights go up.  The heavier the kiddos were, the lower the risk, all the way up to >4500g (that's 9 pounds, 15 ounces).  Low birth weight also translated into a higher risk for all mental disorders, including an aggregate "all diagnoses" group and for each subgroup of  substance abuse,  mood disorders (like major depression and bipolar disorder), and anxiety disorders.  And, indeed, in the subgroups, the higher the birth weight (all the way up to the megababy 10 pounder and above group), the lower the risk.


Interesting!  Obviously, very low birth weight is associated with all sorts of issues - premature delivery, infection, brain hemorrhages - any or all of these could have stress on the baby's forming brain.  It is interesting that the heavy babies had lower risk than the so-called normal weight babies.  I actually would have expected another "U-shaped" curve here.  But no!  Still, there could be huge confounders. High birth weights are associated with gestational diabetes, but I'm not sure how common that was in Sweden and Denmark back in the 70s and 80s, so maybe it wouldn't be as much of a factor as I would have thought.  

One of those confounding factors could actually be vitamin D!  This study showed maternal vitamin D intake associated with birth weight (low vitamin D = lower average birth weight), and it was postulated that adequate vitamin D intake protects moms from infections.  This study is a little more interesting - white women with a vitamin D level from 60-80 had the lowest risk of having small for gestational age babies, but there was no relationship between vitamin D levels and birth weight in black women.  And, of course Don Matesz blogged today about this study, showing that pregnant women who took 4000 IU vitamin D daily had a lower risk of preterm birth.


All told, several interesting findings this month.  Don't get vitamin D deficient!  But try not to go nuts with the supplementation either.  Levels are best!  Ask your doctor, or go to Grassroots Health to order a home test.  I tend to aim for a level of 50, but perhaps pregnant women would want to go just a bit higher (Caucasian women may want to aim for that 60-80 range).  Be sure you are getting your K2 also!  I always use pastured butter, but I also have a vitamin D supplement that comes with K2 in it. 

Believe it or not, there is another blog-worthy study in this month's Archives, but I will save it for later in the week.  See you then!

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Autism and Vitamin D

Vitamin D researcher Dr. John Cannell is all over this one, so I don't need to reinvent the wheel here.  I'll hit the highlights and link his articles for the full discussion.  His 2007 article (thank you, Jamie, still commenting and sending amazing articles and links from a disaster zone!) may be familiar to some of you from the vitamin D council website, but he printed an updated article available on pubmed central in August of 2010 reviewing all the new research between 2007 and now.  Hooray!

Cannell's 2007 article

Update, August 2010

His major points (he has several more, but I'll put up some of the more compelling ones):

1) Autism is increasing, as is vitamin D deficiency, and the autism epidemic came upon us at the same time the major health authorities advised us to eschew the sun.

2) Vitamin D is likely central to brain development as a key helper in neural development and neuroprotection.  In addition, autism is likely mediated by inflammation, and vitamin D is a key player in anti-inflammatory processes.  Also, vitamin D enables glutathione, the "master antioxidant," clear our system of free radicals, and glutathione also acts as a chelating agent to bind toxic heavy metals such as mercury, which kids with autism have a tough time clearing from their systems.

3) Williams syndrome, a chromosomal disease which (among other things) results in abnormally high levels of circulating active vitamin D in early childhood, results in kids who are especially social and overfriendly - rather the opposite of autism symptoms.

4) During pregnancy, boys' brains are bathed in testosterone, and girls' brains in estrogen.  Estrogen is known to have many vitamin D enhancing properties.  This could account for the 4:1 ratio of boys to girls suffering from autism.

5) Studies show autism births occur most often in March, at the end of winter, when vitamin D levels would be lowest.

6) African Americans seem to suffer from a higher rate of autism, and they also have a higher rate of vitamin D deficiency than people with lighter skin.  In Europe, the children of darker-skinned immigrants have higher rates of autism also.

7) Rickets, due to vitamin D deficiency, is characterized by hypotonia (poor muscle tone) and developmental delay, as is autism.

8) Autism seems to be higher among the kids of highly educated women, and they are more likely to follow guidelines for sun restriction for themselves and their children.

All told, it makes for a compelling theory, and Dr. Cannell has a point in that "this theory deserves immediate attempts to disprove it."  My only major issues with it are that rickets is not autism, and that there may not be a new autism epidemic after all, but we are only now recognizing how prevalent the disorder actually has been all this time.  But I could certainly be wrong about that second bit.  And, by all means, let's please give pregnant women guidelines for sufficient vitamin D and get the kids to play outside!  And let's study vitamin D and autism directly.

Dr. Cannell touches on this next part in his 2010 article, and it is part of one of the overriding themes of my blog - we have a lot to learn from history.  If vitamin D deficiency is the cause of autism, then all of this has happened before.  Rickets, characterized mostly by bone growth abnormalities in children, became endemic during the industrial revolution, when people in cities, especially, seemed to spend very little time outdoors, diets were poor, and many children died, as there was no cure.  Eventually, cod liver oil and sunbathing were shown to prevent and improve the disease.

Here is Dr. Cannell's quote:  "If adequate amounts of vitamin D prevent autism, one would expect children with rickets to have an increased risk of autism. To my knowledge, the neuropsychiatric symptoms of rickets have not been studied in the modern era. However, at least two old papers have addressed it, both published before Kanner described autism in 1943. Both papers describe �weak mindedness,��feeble minds,��mental dullness,� unresponsiveness and developmental delays. Even more intriguing, both papers report that the mental condition in rickets improved with vitamin D."

Those papers, Hallerhan MM. The effect of rickets on the mental development of young children. Arch Psychol. 1938;229:1�67, and Gilmour A. The mental condition in rickets. School Hygiene. 1912;9:6�16, are not available online, but may be worth trying to get a look at (if I can find my library ID.  We are certainly spoiled in the internet age!)

I do happen to have handy a copy of Nutrition and Physical Degeneration, first published in 1939, and here is what he had to say about the state of mental health at the time (1):

"Many of our modern writers have recognized and have emphasized the seriousness of mental and moral degeneration. Laird has made a splendid contribution under the title "The Tail That Wags the Nation,"  in which he states:

    The country's average level of general ability sinks lower with each generation. Should the ballot be restricted to citizens able to take care of themselves? One out of four cannot. . . . The tail is now wagging Washington, and Wall St. and LaSalle Street. . . . Each generation has seen some lowering of the American average level of general ability.

    In Laird's analysis of our present situation he has stressed a very important phase. While emphasizing that the degeneration is not limited to restricted areas, he raises the question as to whether local conditions in certain areas play important roles in the rate and extent to which degeneration has taken place. He says further,

   Although we might cite any one of nearly two dozen states, we will first mention Vermont by name because that is the place studied by the late Dr. Pearce Bailey. "It would be," he wrote, "safe to assume that there are at least 30 defectives per 1000 in Vermont of the eight-year-old mentality type, and 300 per 1000 of backward or retarded persons, persons of distinctly inferior intelligence. In other words, nearly one-third of the whole population of that state is of a type to require some supervision."

The problem of lowered mentality and its place in our modern conception of bodily diseases has not been placed on a physical basis as have the better understood degenerative processes, with their direct relationship to a diseased organ, but has generally been assigned to a realm entirely outside the domain of disease or injury of a special organ or tissue. Edward Lee Thorndike, (8) of Columbia University, says that "thinking is as biological as digestion." This implies that a disturbance in the capacity to think is directly related to a defect in the brain."

* * *

Of course, at the time, they did not have the diagnostic categories to differentiate between the varieties of autism, mental retardation (most commonly due to hypothyroidism at the time), and cerebral palsy. But there they were, recognizing that mental illness was biological, way back in the early part of the century.  Pretty good considering that psychiatry is something of the red-headed stepchild of modern medicine even today.  

It does make you wonder.  This "mental degeneration" of that time period, in part, led to the rise of eugenics, and even Nazis.  In the late 1800s, admissions to mental asylums skyrocketed.   The mental health of the western world seemed to improve after World War II, when bread began to be fortified with B vitamins, and people recognized the importance of at least a small amount of vitamin D.  But anxiety, depression, and "bodily degeneration" is on the rise again with our change to industrial processed food, and maybe autism as well.

In historical novels, a curative practice for what ails you is always to take some time visiting on the seashore.  One would expect to get more sun then, and eat more nutrient-rich seafood.  Sounds like a good plan to me.

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D-D-Depression

I was deficient in vitamin D. Of course. I paid attention to the official word about sunshine - it's bad for you. Ultraviolet radiation chops up your skin cell DNA, and with enough scrambled DNA and a bit of bad luck, you will eventually get cancer. There are several major types of skin cancer, but melanoma is the scariest, also, sun gives you wrinkles and age spots and... so I've been putting on sunblock and avoiding the beach except for a few days a year for a least 10 years.

At the same time the dermatologists and women's magazines were scaring us away from the sun, our own fat phobia and a cultural trend of eating less organ meat scared us away from the best dietary sources of some key fat soluble vitamins (A, D, E, and K). We don't want to be low in these vitamins, as they tend to help orchestrate a lot of functions in the body. Vitamin D (which is found in animal fats, but we tend to get about 90% from the sun) in particular seems to be involved in about 10% of the biochemical soupy stuff our body does every day. It has a lot to do with membrane signaling and scavenging up any screwy cells that are starting to go awry (i.e. cancer), and being low in vitamin D seems to put us at hugely increased risk of cancer, including melanoma. And prostate cancer. And breast cancer. And colon cancer. In fact, women diagnosed with breast cancer in the summer and fall have the best prognosis. There are reports of chemotherapy not working as well in the winter. (1)

There are also links to mental health - depression, bipolar disorder, and psychotic disorders (2) have all increased in populations once most people stopped working outside and went to work inside. The elderly with low vitamin D also have much higher rates of depression (3). In this study of bone mineral density and depression, the elderly with poorer bone status were also more depressed (vitamin D was not explicitly stated to be the possible linking factor for both illnesses).

How would vitamin D affect the brain? Vitamin D is involved in the synthesis of the catecholamines (which are highly involved in neurotransmission). Summer sunlight increases brain serotonin levels twice as much as winter sunlight (4). Neurons and glial cells in all kinds of areas of the brain have vitamin D receptors on them, indicating a brain that is hungry to use vitamin D. Some effects in the nervous system include the synthesis of neurotrophic factors (what I call "brain fertilizer"), inhibition of the creation of an enzyme that chews up nitric oxide, and increasing glutathione levels. (See my previous posts for a molecular description of how some of these brain chemicals are thought to be involved in depression). As vitamin D in the periphery is associated with scavenging and cleaning cancer cells, vitamin D in the central nervous system seems to be involved in detoxification and anti-inflammatory pathways (5)(6).

Does supplementation help depression? Well, the first several studies were disappointing. Harris and Dawson Hughes tried treating Seasonal Affective Disorder with 400 IU vitamin D2 daily. Didn't do squat. Of course, D2 is the plant form of vitamin D (the animal form is D3), and 400 IU is a tiny dose anyway. Lansdowne and buddies gave 400 IU and 800 IU of vitamin D3 to healthy subjects in late winter, and found a lightened mood in those receiving the supplements. Hollis gave people with seasonal affective disorder a single 100,000 IU dose of D3, and found it to be more effective than light therapy, and the improvement was statistically correlated with the improvement in serum 25(OH) vitamin D levels. In this intriguing study, young adults were given access to tanning beds on Mondays and Wednesdays. One bed had UV light, and identical bed didn't. On Fridays, the participants were allowed to choose which bed they wanted. 95% of the time, they chose the UV bed, and participants also reported being more relaxed after a UV tan than in the sham bed.

Unfortunately, there is no large, well-designed study of D3 supplementation for depression that I'm aware of. However, there is enough interesting evidence for such a trial to be done, especially in populations that are more likely to be vitamin D deficient, such as the elderly. Like fish oil, vitamin D3 is cheap (about $10 for a three month supply) and readily available. And given the links to other diseases also (heart disease, stroke, osteoporosis, kidney damage, hypertension, you name it (1)), it would seem prudent (and money-saving from a public health standpoint if a lot of cancer is really prevented by adequate supplementation) to test for and treat deficiency in people with psychiatric disorders.

Another issue is that the RDA for vitamin D is woefully small. About 400 IU daily. This is an amount that will keep you from getting rickets, but it's certainly not an optimal amount for humans. I've heard murmurings that the official RDA is going to be increased to 1000 IU daily, and most decent multivitamins will have 1000 IU of vit D already (that's why your multi says "250%" of RDA of cholecalciferol (vit D3), in case you were wondering). The amount in fortified milk is also small, so that one would need to drink a truckload for it to matter much.

So how much vitamin D do we need, and hey, isn't vitamin D a fat soluble vitamin, which means we can store is for a long time, and couldn't we get toxic from high amounts? The answer is - we probably need many times the current RDA for vitamin D to get reasonable serum levels of the stuff, and yes, we can get toxic, but for most people that is not a realistic worry.

According to the Vitamin D Council, a serum level of 50 ng/ml or higher of 25 (OH) vit D3 is optimal. This level is not without controversy, and 35 is accepted by most as the minimal acceptable level. One probably doesn't want to go above 100, though toxicity has only been reported at serum levels higher than 150 (6). You can't get too much vitamin D from the sun - our skin actually destroys excess vitamin D made there after you have enough for the day. A cool regulatory mechanism if ever I heard one. You *could* theoretically get toxicity from combining high amounts of supplementation *and* lots of sunshine. There's a description on the vitamin D council website of one guy who actually did get toxic from supplements - turned out an industrial accident made his particular variety of vitamins (Prolongevity) contain up to 430 times the amount on the label. This guy was taking between 50,000 IU and 2.6 million IU daily for about two years. He recovered (uneventfully) with some medicine and sunscreen.

So how do you know if you have enough vitamin D? Well, if you are a lifeguard in Miami, you're probably fine. If you have very dark skin, unless you are a lifeguard on the equator, you probably need some supplementation. It can take someone with very dark skin about 5-6 times longer in the sun to get enough vitamin D to have adequate levels compared to someone with very pale skin. If you live north of 40 degrees latitude (above New York City), you only have a few weeks in the summer to expose that skin and get the full amounts of vitamin D you need to last you for the year, and you may have to supplement (again, there is controversy about this, especially as very pale people of Northern European ancestry seemed to live to the far north of 40 degrees and had only a few days a year they could possibly get adequate vitamin D from the sun). Anyway, to really know your blood levels of vitamin D, you need to get a blood test. The key level you need to know is 25-OH vitamin D3. If your doctor orders 1,25 OH or just "total vitamin D" you might not get the right number, so make sure you look at the lab slip. If you don't want to go to the doctor, you can go to this website and pay $65 or so for a home testing kit. Unless you live in New York state, where home testing via mailing bloodspot cards is apparently illegal.

So let's say you ordered a home test kit and stabbed your finger and shipped your spot of blood back to the lab and your level comes out to be 31 ng/ml. There's a general rule of thumb that 1000 IU of supplementation daily will increase blood levels by 10 ng/ml. (Use geltabs in oil suspension rather than tablets, unless you are always going to be taking the supplement with some oil/fat.) So let's say we are aiming for 50 - then one could take 2000 IU D3 daily in the morning. If you were already supplementing at 1000 IU (in your multivitamin, for example), you could take an additional 2000 IU daily, and you could skip the additional supplementation on days you spent time in the sun (without suncreen - sunscreen will block the UVB rays that synthesize vitamin D in the skin). Arms and legs exposure for 20 minutes midday in the summertime in Boston about 3-4 times a week would get you a goodly amount (probably around 10,000-12,000 IU with each exposure) if you have pale skin. That kind of exposure is not such a big deal for skin cancer risk, as long as you avoid burning. The farther south you are (until you get to the equator, then reverse!) and the paler you are, the less time you need.

It is standard practice for physicians to treat vitamin D deficiency with 50,000 IU pills once a week for 8-12 weeks, then recheck. Unfortunately, a recent JAMA study of similar treatment in elderly women (admittedly it was 50,000 IU D3 daily for 10 days) resulted in a great increase in the number of fractures. The editorial for the study thought 4000 IU daily was a safer, more physiological amount to treat deficiency, and be sure you are getting adequate calcium too. However, if you supplement with calcium and vitamin D3, as your vitamin D levels become adequate, your absorption of calcium can increase quite a bit (see slides 18-36). Therefore, you may not need as much calcium if you take vitamin D. The recommendations are not set in stone, though. (Our current RDA for calcium may be high simply because we don't get enough vitamin D!) Also, most of the prescription vitamin D doses are D2, not D3, and D2, the plant form, is probably not nearly as effective as the animal-derived form, D3.

Here's yet another thing to watch out for with higher-dose vitamin D3 supplementation. Occasionally, you will unmask some hyperparathyroidism. If someone's parathyroid is working on overdrive, he or she will start to have serum levels of calcium that are way too high, potentiated by the higher doses of vitamin D3. This can be dangerous if it goes undetected, though high calcium levels can be very uncomfortable, with symptoms of muscle twitching, cramping, fatigue, insomnia, depression, thinning hair, high blood pressure, bone pain, kidney stones, headaches, and heart palpitations. Since bone pain, fatigue, depression, and insomnia can be symptoms of low vitamin D3 as well, it is important to realize that if your symptoms get worse with supplementation, you should see your doctor and get a calcium and parathyroid hormone checked. While I personally don't check calcium levels with the initial vitamin D level, I do check it for follow-up ones (I tend to check after three months or so). While home testing is a neat option for the initial level, seeing your doctor about follow up and his or her suggestions for supplementation is a good idea if your level is found to be low.

And what about those other fat soluble vitamins: A, E, and K? It is important that you have enough of each of them, or things can get a bit screwy. For example, in order to create bone, you need adequate vitamin D (at least a level of 20-30), adequate calcium, AND vitamin K2. The best sources are animal fats, particularly the fats from animals that eat their natural diet - grass for cows, or grubs and grains and whatnot for chickens. So pastured chicken egg yolks, and butter and liver from pastured cows. Conventionally-raised eggs can have about 1/20th the vitamins of pastured eggs, and butter from grain-fed cows may have as little as 1/200th as much K2 as pastured butter, so it really does matter what the animals you eat ate. Vitamin A is also found in multivitamins and it is important not to have too much vitamin D3 and too little A, so I've recommended a multivitamin in addition to vit D3 for people who are deficient in serum 25 (OH) vitamin D (and aren't big liver eaters :)).

Strict vegetarians - here's another place you need to be super careful about what you eat, and you might need to choke down some fermented soy products (netto) to get enough Vitamin K2. K2 isn't found in a standard multivitamin (though we can make K1 into K2, if our intestinal flora is happy, which it might not be on a standard American diet - no idea about flora in a vegan diet. Interesting question) and is vital to bone formation and in keeping our arteries resilient. K2 is what warfarin blocks, so don't take it if you are on coumadin for blood clots. (Though why are you at risk for blood clots in the first place? maybe too much omega 6 compared to omega 3??)

So, a key part of good, lasting health is either to get plenty of (safe - no burns!) sun as our ancestors did, or use today's science to get your blood levels of vitamin D where they need to be. Chat with your doctor about it - and check out the Vitamin D Council Website for more information.

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