Wednesday, April 26, 2017

Non-wheat grains that are high in glycine betaine (trimethylgycine)

Cereals and pseudocereals (i.e., edible grains) are typically the main source of glycine betaine (trimethylgycine or TMG) in human diets. (http://www.sciencedirect.com/science/article/pii/S0308814613012247)  (Whether we can easily use that TMG appears to depend on food preparation methods, as discussed here.) Wheat germ and bran have especially high TMG content. Unfortunately, many people now avoid eating wheat due to concerns about gluten or a desire to lose weight via a low-carbohydrate diet. Some Serbian researchers realized avoidance of wheat might cause a deficiency in dietary TMG and investigated the TMG content of other grains. They posted their results in a paper available online here.

Here's the abstract:

In this study, betaine [TMG] content in cereal grains, cereal-based products, gluten-free grains and products of mainly local origin was surveyed. Estimates of betaine are currently a topic of considerable interest. The principal physiologic role of betaine is as an osmolyte and methyl donor. Inadequate dietary intake of methyl groups causes hypomethylation in many metabolic pathways which leads to alterations in liver metabolism and consequently, may contribute to numerous diseases such as coronary, cerebral, hepatic and vascular. Cereals are the main sources of betaine in human diet. Results showed that betaine content in grains is variable. Spelt grain was found to be a richer source of betaine (1848 mg/g DM) than that of common wheat (532 mg/g DM). Gluten-free ingredients and products were mainly low in betaine (less than 150 mg/g DM). Amaranth grain is a remarkable gluten-free source of betaine (5215 mg/g DM). Beet molasses is an ingredient which may increase betaine content in both cereal-based and gluten-free products.

http://fins.uns.ac.rs/e-journal/index.php?mact=Magazines,cntnt01,details,0&cntnt01hierarchyid=35&cntnt01sortby=magazine_id&cntnt01sortorder=asc&cntnt01summarytemplate=current&cntnt01detailtemplate=detaljno&cntnt01cd_origpage=178&cntnt01magazineid=174&cntnt01returnid=188

I highly recommend reading the entire paper if you're at all interested in this topic. I'll pull out what I consider the highlights:

Rice contains no TMG. Corn, millet, and buckwheat have a little TMG, and oats and barley have a little more. Good sources of TMG include wheat (spelt wheat is best, and bread wheat has more than durum) and rye. Amaranth and quinoa have very high levels of TMG, as does beet molasses.

I pestered a Belarussian relative recently to find out whether she eats a lot of borscht and beet greens. She said, no, that's more her mom and aunt who do that, but she drinks kvass often. Kvass is a rye bread-based beverage popular in eastern Europe. Rye has about four times the amount of TMG as wheat. Sadly for me, kvass is mildly alcoholic, and I don't drink alcohol for religious reasons. (I'd love to play with a reverse osmosis filter that could allow me to make my own de-alcoholized drinks, but from what I read online, such an apparatus is hard to come by.)

Amaranth used to be a very popular grain in Guatemala, Mexico, and Peru. Amaranth has been becoming a regularly-consumed pseudocereal again in the past couple decades, but it's happening very, very slowly. I started putting a tablespoon full of amaranth in with my batch of rice in the rice cooker in order to get more TMG in our family diet; my family doesn't notice the addition.

I've liked quinoa since I was sixteen. I think my dad was introduced to quinoa while on a trip to Machu Picchu, and he ate it like it was couscous, complete with canned spaghetti sauce over it. It tastes quite good that way, especially with some grated cheese on top. In the Andes, quinoa is mostly eaten in soups and porridges. I think it's unfortunate that we tend to drain our quinoa here in the USA, for that disposes of the TMG that leaches out into the cooking water.

Beet molasses is marketed as a bread topping in Germany. A German friend brought me some a couple of weeks ago, and it is quite tasty. I'll have to look for it in our local German deli/market after I run out. Which will be in about 2-3 more weeks, based on how quickly we're eating it. It's rather like pancake syrup, but one feels healthier eating it due to the knowledge that it is high in TMG.

Tuesday, April 18, 2017

Wheat as a source of trimethylglycine (glycine betaine)

As referenced earlier, here is a post on bulgur. I'll also talk a little about steamed buns and boiled wheat generally.

In the USA and western Europe, we eat a lot of wheat (although western Asia surpasses even our high consumption - http://www.fao.org/docrep/006/Y4011E/y4011e04.htm). We eat our wheat primarily in two forms: 1) moderately-wet dough baked at relatively high temperatures over/in dry heat and 2) boiled-then-drained noodles. The first method of preparation lacks long periods of significant amounts of water molecules energetically vibrating in and around and breaking down plant cell walls, which would mean less TMG becomes freed. The second method obviously includes boiling water, but the trimethylglycine (TMG) dissolved into the boiling water (typically around 60-80% of food's TMG content - http://www.sciencedirect.com/science/article/pii/S0308814603000633) is subsequently drained away.

Why do we like our wheat products so dry in the USA? Bread, buns, crackers, cookies, pizza, drained pasta, bran flakes, and so forth are convenient, less messy, and store well. In medieval times, the countries of western Europe used to eat gruel and porridge made of high TMG grains like wheat and rye, however, except for oats, porridge has mostly fallen out of favor in those regions.

Yet in other--usually much poorer--parts of the world, wheat is still prepared in ways that allow for consumption of easily-absorbed TMG. Bulgur wheat is a parboiled-then-dried cracked-wheat product that is prepared at home for consumption by being placed in very hot/boiling water until the water has been absorbed. The water is sometimes drained away afterward, but it is not drained away when bulgur is utilized in pilaf dishes, which are intentionally made so as to absorb all the cooking liquid. The parboiling, or partial cooking, process is often carried out with steam rather than actual boiling. Parboiling retains enough nutrients that bulgur is classified as a whole grain product. Thus bulgur is twice treated with steam/hot water, which helps release TMG from the bulgur's cell walls without carrying it all away, while the nutrients in the water used to prepare bulgur are usually retained and ingested.

Look at which countries and cultures are eating large amounts of bulgur. They're the ones all around the Mediterranean, especially Turkey and the region called "the Levant." These countries also don't seem to have much of a societal burden from autism. Other societal burdens, they have aplenty. But not autism. Remember the low autism prevalence in Israel and how it was lowest of all for rural Israeli Arabs? And over in Turkey, despite evidence that medical and nursing schools there are doing a good job of teaching their students about autism (https://www.ncbi.nlm.nih.gov/pubmed/27524519), Turkey simply is not dealing with the same levels of autism as the US and western Europe (http://www.tpfund.org/2013/03/lets-talk-about-autism-in-turkey/).

Eastern Asia generally eats less wheat than Europe and western Asia, but in Chinese-influenced cuisines, it's normal to eat that wheat in steamed buns, dumplings, and noodle soup. Western-style bread, while becoming more popular, is not normally a staple of eastern Asian diets. (https://chinafoodingredients.wordpress.com/2014/05/19/bread-in-china-from-snack-to-staple-though-for-the-young-urban/) The steaming process seems as it if would help break down cell walls to allow the egress of TMG while not carrying it away as full-on boiling would do. Where dumplings and noodles have been cooked in soup, TMG leaching from them into the soup broth will end up being ingested. China also consumes a lot of stewed spinach and other greens, so I suspect that its traditional cuisines include enough easily absorbed TMG to protect to some degree against autism. Unfortunately, data about autism in China are currently considered inadequate. (https://molecularautism.biomedcentral.com/articles/10.1186/2040-2392-4-7) (I wouldn't be surprised if the Chinese data turn out to be pretty accurate in the end. I've never understood why autism-awareness advocates online insist that the other countries of the world are all misdiagnosing children if they don't find the same rate of autism as the USA. That seems arrogant.)

My takeaway from this? Ingest liquids in which wheat was cooked. To quote an online cooking writer, "when you dump the remaining pasta water down the drain, that's where you make the pasta gods cry." (http://www.cookinglight.com/cooking-101/your-pasta-water-is-liquid-gold)

Sunday, April 2, 2017

It's time to end the autism epidemic (Conclusion)

I didn't intentionally set out to end this blog series on Autism Awareness Day. These ideas have been percolating in me for over a year, but it is fitting that I finish on a day when the world's attention is turned to autism spectrum disorders (ASD).

Some have begun turning Autism Awareness movements into a celebration of being neurodiverse and so deflected attention from finding what is causing the rise in autism in order to stop the "epidemic." (I use quote marks because epidemics are of infectious diseases, and autism spectrum disorders are not contagious.) I'm what I would consider a mild case of "Asperger syndrome," and I experience both the good and bad of being on the autism spectrum: the ability to focus (obsess even) and shut out people around me, the bent towards abstract subjects like math and linguistics, and the delay in social skills that made me an easy target as a child for bullying peers. This form of high-functioning autism runs in my family and affects the males more than the females, often disrupting their ability to have productive relationships. Autism-connected disruption in social skill development is not something to celebrate; it's something to address, ameliorate, and prevent if possible.

The evidence I have cited in this series indicates that we can prevent a large percentage of cases of ASD in the USA by 1) replacing cyanocobalamin and folic acid with other forms of vitamin B12 and folate, and 2) consuming more glycine betaine (TMG) in easily absorbed ways during pregnancy and early childhood.

Thank you for reading. If you think the research and connections I have presented have merit, please spread the word. 

C. Taylor, JD

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Saturday, April 1, 2017

It's time to end the autism epidemic (part 4)

In part 1 of this blog series, I approached the problem of autism spectrum disorders (ASD) like a computer programmer looking for a programming glitch. The best output data available point to a problem in the homocysteine-methionine cycle being involved in approximately 95% of autism cases. (Because autism diagnoses criteria are still subject to some debate, I wouldn't expect us to ever find a 100% correlation between any one physical process and autism.) Recent findings, outlined in parts 2 and 3, indicate that autism development is more specifically linked to the methionine synthase (MS) homocysteine-to-methionine pathway. Having formulated a hypothesis that methinone synthase dysfunction is involved in autism, I next developed a testable prediction based on the existence of an alternative homocysteine-to-methionine pathway catalyzed by the enzyme betaine-homocysteine methyltransferase (BHMT). My prediction is that nutritional support of BHMT activity will partially make up for MS dysfunctions and in that way protect against developing an autism spectrum disorder. Let's examine whether the data support that prediction.

First, BHMT is a zinc-containing enzyme, so having enough zinc in one's body should correlate with a lower ASD risk. That does indeed appear to be the case. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100031/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563033/, https://www.ncbi.nlm.nih.gov/pubmed/26218250)

Second, BHMT requires glycine betaine (trimethylglycine or TMG) as a substrate. What is TMG?
Betaine is found in microorganisms, plants, and animals and is a significant component of many foods, including wheat, shellfish, spinach, and sugar beets. Betaine is a zwitterionic quaternary ammonium compound that is also known as trimethylglycine, glycine betaine, lycine, and oxyneurine. It is a methyl derivative of the amino acid glycine with a formula of (CH3)3N+CH2COO and a molecular weight of 117.2, and it has been characterized as a methylamine because of its 3 chemically reactive methyl groups. Betaine was first discovered in the juice of sugar beets (Beta vulgaris) in the 19th century and was subsequently found in several other organisms. The physiologic function of betaine is either as an organic osmolyte to protect cells under stress or as a catabolic source of methyl groups via transmethylation for use in many biochemical pathways.

http://ajcn.nutrition.org/content/80/3/539.full; Craig SAS. "Betaine in human nutrition." Am J Clin Nutr 2004;80(3):539-549.

Here's a listing of the some of the best sources of TMG:

Food itemBetaine content
mg/100 g
Wheat bran1339
Wheat germ1241
Spinach600-645
Beets114-297
Pretzels237
Shrimp219
Wheat bread201
Crackers49-199
http://ajcn.nutrition.org/content/80/3/539/T1.expansion.html

The very best sources of TMG are mussels, clams, oysters, and scallops, but due to cost and convenience factors they tend not to be commonly-eaten components of cuisines in areas with reported statistics for autism prevalence. Moreover, it is not clear just how much TMG is actually available during digestion from unpulverized mussels, oysters, clams, and scallops, all of which when cooked whole are too often rubbery and difficult to chew. So I will have to pass shellfish by and look at plant sources of TMG.

Inside plant cells, TMG functions as an osmoprotectant (https://academic.oup.com/jxb/article/51/342/81/485733/Genetic-engineering-of-glycinebetaine-synthesis-in), and in onions TMG has been demonstrated to protect cell membranes against NaCl-induced membrane permeability. (http://cat.inist.fr/?aModele=afficheN&cpsidt=2422100) Hence, it is to be expected that methods of vegetables and grain preparation which rupture plant cell membranes would be more effective at freeing TMG for human dietary absorption than would other food preparation methods that tend to leave TMG-protected plant cell membranes intact. It has been found that boiling is highly effective at removing TMG from foods and that the TMG is largely recoverable from the liquid that the food was boiled in (http://www.sciencedirect.com/science/article/pii/S0308814603000633). Free TMG in an aqueous solution and liberated from its original plant cells should be the most easily-absorbed of all TMG dietary sources. The highest levels of TMG in plant sources are found in wheat bran and germ, spinach, and Beta vulgaris (beetroot and chard).

Which regional cuisines have high amounts of boiled wheat bran and wheat germ? Wheat gruel has fallen out of popularity in the wheat-eating parts of the world in the past couple of centuries. We do boil pasta, but the pasta is often manufactured so as to be mostly devoid of wheat germ and bran. Also, during the boiling of pasta, most of its TMG content leaches into the water and is subsequently dumped down the drain instead of being ingested. (Update 4/8/2017: I overlooked the use of cracked wheat--or bulgur--in many countries and cuisines, so here's a post about it. And here's a post discussing non-wheat grains that are high in TMG.)

What about spinach? I know of only one major regional cuisine that frequently utilizes boiled spinach together with the liquid in which it was boiled. That region is that of northern India and Pakistan, where they often eat palak (spinach) puree dishes; in the USA, this puree can be found in the Punjabi dish palak paneer. Due to poverty and health care issues, autism statistics in all of India are not clear. But a recent study out of the Punjab region (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943381/) found an ASD prevalence of merely 0.9/1000 (1 in 1,111). In comparison, the ASD rate in the USA is 14.6/1000 (1 in 68) (https://www.cdc.gov/mmwr/volumes/65/ss/ss6503a1.htm).

And what about beets? Beets are actually what brought me to see the importance of TMG in preventing autism. I lived in Poland, and I know how important a part of their cuisine beetroot is, especially cooked into a strained borscht-like soup called "barszcz cerwony." Did you catch that? Strained. That means barszcz czerwony is simply full of TMG and doesn't include any plant fiber to decrease the TMG percentage of the soup. If my hypothesis is correct, then Poland should have a very low autism prevalence. And Poland apparently does, per a 2015 study of health records:
The National Health Fund reported that 13 261 individuals up to 18 years of age received health services for autism and related disorders in Poland in 2012. This is a prevalence rate of 3.4 cases per 10 000 individuals. Incidence rates vary in different Polish regions, with the highest rates recorded in the following voivodships: warmińsko-mazurskie (6.5 cases per 10 000 individuals), śląskie (5.0), and pomorskie (4.6). The provinces with lowest rates were podlaskie (2.1), małopolskie (1.9), zachodniopomorskie (1.9), and łódzkie (1.8). These rates are far lower than those in European countries (20 per 10 000) and United States (200 per 10 000) epidemiological surveys.

http://www.sciencedirect.com/science/article/pii/S1230801315000119

Despite having guaranteed health care for all Polish children, Poland appears to be diagnosing ASD in only .34/1000, or 1 in 2941, children. Can the USA really have approximately 40 times more children with ASD than Poland? Perhaps the Polish people, due to language and training differences, just don't know about autism? That is highly unlikely. There have been Polish universities offering English-language medical school programs for over twenty years. And Poles themselves, including Polish doctors, have been working in the United Kingdom (UK)--where autism is certainly well-known--in large numbers since Poland joined the European Union (EU), which enabled its citizens easily to work in other EU countries.

If the beetroot soup and other beet consumption is protecting the Polish children from developing ASD, then other countries and cultures that often eat borscht and the juice of boiled beets should have lower rates of ASD. And they do.


Other countries that eat borscht as part of their traditional cuisines include Russia, Belarus, Romania, and Lithuania, for all of which we lack clear statistics about ASD prevalence. Based on my interactions with people from eastern Europe, autism seems to be be much less of a problem for their societies than it is for western Europe and the USA currently (https://www.autismspeaks.org/science/science-news/europe-gets-active-autism).

The evidence above bears out my prediction that high levels of free TMG in the diet will protect against development of autism spectrum disorders. One counterclaim that could be made, though, is that genetics might actually be behind the lower rates of ASD in the above-cited regions and cultures, but I do not consider that a strong argument because much of the US population is of partial or full Germanic ancestry, either from Germany or via English heritage. Moreover, I have two young male relatives of half-Slavic background, and only the one born and raised in the USA exhibits ASD symptoms.

In short, I consider the evidence convincing that 1) a dysfunction involving methionine synthase is causally connected to autism spectrum disorders, and 2) high consumption of easily-absorbed glycine betaine protects against developing autism spectrum disorders.

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Friday, March 31, 2017

It's time to end the autism epidemic (part 3)

Besides 5-MTHF, we need a sufficient supply of methylcobalamin (MeCbl), a form of cobalamin (vitamin B12), in order to support methionine synthase (MS) function. There are four kinds of vitamin B12 available as supplements: methylcobalamin, adenosylcobalamin, hydroxocobalamin, and cyanocobalamin (CnCbl). Only methylcobalamin and adenosylcobalamin occur naturally in our bodies, and we normally get them from animal products. Hydroxocobalamin is produced by bacteria and then is made stable synthetically by using cyanide to change it from hydroxocobalamin to cyanocobalamin. Cyanocobalamin is the form of B12 typically put into multivitamins and fortified foods.

What happens when we ingest methylcobalamin? Unfortunately, it doesn't seem to go straight to where it might be needed in the body. A complex processing of B12, which is still the subject of investigation, happens in the cells first. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692085/, https://www.ncbi.nlm.nih.gov/pubmed/27771510) Methylcobalamin, adenosylcobalamin, and cyanocobalamin all undergo separation of the non-cobalamin part from the cobalamin part by the protein MMACHC. MMACHC catalyzes the decyanation of cyanocobalamin and the dealkylation of methylcobalamin and adenosylcobalamin, after which the cobalamin is chaperoned (cobalamin is very volatile on its own) and changed to adenosylcobalamin and methylcobalamin. The transformation of cobalamin to methylcobalamin, based on recent findings, appears to be part of an interplay of several proteins, including both MMACHC and methionine synthase (MS). (https://www.ncbi.nlm.nih.gov/pubmed/27771510) In other words, a problem with MS could not only affect MS in its homocysteine-salvaging function but could also make MeCbl less available to due to MS interacting with MMACHC, which decyanizes cyanocobalamin.

If you've ever read about chaos theory, you probably saw a mention of feedback loops. Feedback loops are an important principle to understand when dealing with systems of complex interactions such as those involving MS and B12 transport, conversion, and use.
The term feedback refers to a situation in which two (or more) dynamical systems are connected together such that each system influences the other and their dynamics are thus strongly coupled. Simple causal reasoning about a feedback system is difficult because the first system influences the second and the second system influences the first, leading to a circular argument. This makes reasoning based on cause and effect tricky, and it is necessary to analyze the system as a whole. A consequence of this is that the behavior of feedback systems is often counterintuitive.

http://authors.library.caltech.edu/25062/1/Feedback08.pdf (Feedback Systems: An Introduction for Scientists and Engineers. Karl Johan Åström; Richard M. Murray (2010). "§1.1: What is feedback?" Princeton University Press, p. 1).

I'm not going to try to untangle exactly what is happening between cyanocobalamin, MMACHC, and MS in the human brain, for we lack the necessary knowledge to do so at present. But we have evidence from a paper published last year that the fetal brain, for whatever reason, doesn't break down cyanocobalamin as well as expected.
We found CNCbl to be 15-fold higher in fetal samples, as compared to 0–20 yr old subjects, suggesting unique Cbl metabolism during fetal development. However, the underlying cause of this higher CNCbl level remains unclear, as does the biological origin CNCbl. Maternal folate and vitamin B12 supplementation is a common recommendation during pregnancy, which could be a source of the elevated CNCbl we observed, although Cbl levels in placenta were comparatively low. Conversion of CNCbl to active cofactors MeCbl and AdoCbl requires NADPH- or GSH-dependent decyanation by MMACHC and it is possible that the developing fetal brain has diminished decyanation capacity. The markedly higher level of inactive CNCbl could potentially have functional consequences by competing with MeCbl and AdoCbl, restricting their cofactor activity.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146797 (references omitted).

An excess of CnCbl in the developing fetal brain could be restricting MeCbl activity? Which would negatively affect MS activity? That's exactly what we don't want to have happen if MS dysfunction is behind autism spectrum disorders.

Too little B12 in the brain has been linked to autism. (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146797) And so has an excess of B12, according to the Johns Hopkins findings last year that I mentioned in a previous blog post: "Very high vitamin B12 levels in new moms are also potentially harmful, tripling the risk that her offspring will develop an autism spectrum disorder." (http://www.jhsph.edu/news/news-releases/2016/too-much-folate-in-pregnant-women-increases-risk-for-autism-study-suggests.html) The high B12 levels in the Johns Hopkins study population were almost certainly a result of cyanocobalamin in prenatal vitamins and fortified foods, for naturally occurring B12 forms are unlikely to be consumed at sustained excessively high levels unless one frequently eats clams and liver. (https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/).

Here's the worst part of the finding from the Johns Hopkins study: "If both levels [folate and B12] are extremely high, the risk that a child develops the disorder increases 17.6 times." (http://www.jhsph.edu/news/news-releases/2016/too-much-folate-in-pregnant-women-increases-risk-for-autism-study-suggests.html)

Talk about synergy! Yes, that said 17.6 times the risk of an autism spectrum disorders for children of women who had blood containing too much folate and B12, which almost certainly came from folic acid and cyanocobalamin in their prenatal vitamins and their fortified foods. Both the conscientious mothers who take their prenatal vitamins dutifully and economically disadvantaged mothers who rely on WIC--which generally limits their cereal choices to those that are highly fortified with folic acid and cyanocobalamin--are at risk of having excessive folate and B12, so their children end up at much greater risk of autism spectrum disorders, which are disorders of development, meaning it will be difficult or impossible to fully repair the damage later in life.

The heavy use of folic acid and cyanocobalamin, especially in conjunction, appears to have helped cause the dramatic rise in autism spectrum disorders in the last three decades. Folic acid and cyanocobalamin should be replaced with other forms of folate and B12 that are bioidentical to naturally, commonly occurring forms in order to minimize the hazard of causing unintended problems as has apparently happened with autism spectrum disorders. (I think ADHD is related to this mess, too--https://www.ncbi.nlm.nih.gov/pubmed/27346490--but I'll stay focused on autism for now.)

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Thursday, March 30, 2017

It's time to end the autism epidemic (part 2)

In order to carry out the conversion of homocysteine back to methionine, the enzyme methione synthase (MS or MTR) is dependent on cobalamin (vitamin B12 or Cbl) and folate, specifically in the forms of methylcobalamin (CH3-Clb or MeCbl) and L-methylfolate (5-MTHF, 5-methyltetrahydrofolate, or levomefolic acid). Here's an illustration, showing how the 5-MTHF essentially gives up its methyl group and ends up as plain tetrahydrofolate (THF, another form of folate) while homocysteine is converted to methionine:
https://www.researchgate.net/figure/6580050_fig4_Figure-1-The-cobalamin-dependent-methionine-synthase-catalysed-reaction-CblI

We need sufficient 5-MTHF to keep methionine synthase operating. Where does 5-MTHF come from? It's a form of folate that is produced by the enzyme methylene tetrahydrofolate reductase (MTHFR), and the gene that produces MTHFR has the same name. The body cycles through different forms of folate. Here's an illustration of that "folate cycle":
Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients.
Spellicy CJ, Northrup H, Fletcher JM, Cirino PT, Dennis M, Morrison AC, Martinez CA, Au KS - PLoS ONE (2012) https://openi.nlm.nih.gov/detailedresult.php?img=PMC3515551_pone.0051330.g001&req=4
A deficiency in 5-MTHF can apparently be caused by at least three things:

1 - A deficiency in total folate diminishes the amount of 5-MTHF that can be made from other forms of folate.
  • Defective folate transport can result in autism spectrum disorders and other developmental disorders, and treatment with folinic acid (a form of folate) has been effective in in many children to reverse some autism symptoms. (https://www.ncbi.nlm.nih.gov/pubmed/26924398)
2 - MTHFR gene polymorphisms can decrease the ability of the body to produce 5-MTHF, production of which is catalyzed by the MTHFR enzyme, because the variant genes result in MTHFR enzymes that are more prone to being inactivated by heat. (https://www.ncbi.nlm.nih.gov/pubmed/10201405)
3 - High folic acid consumption causes a pseudo-MTHFR deficiency in mice and so might do the same in humans. (http://ajcn.nutrition.org/content/early/2015/01/07/ajcn.114.086603) Folic acid thus appears highly likely to be a sub-optimal form of folate for preventing 5-MTHF deficiency.
The third point is still controversial because there is research that has found folic acid prenatal supplements help prevent autism specifically where the MTHFR polymorphism associated with autism is present. (https://www.ucdmc.ucdavis.edu/publish/news/newsroom/6677). How does this square with the research I cited that finds autism risk appears to go up when there is excess folic acid? The key word is "excess." Our bodies can handle a little folic acid, but too much can get in the way of making 5-MTHF. I suspect folic acid does this by partially inhibiting the enzyme dihydrofolate reductase (DHFR), leaving more dihydrofolic acid (DHF) to get in the way of the MTHFR enzyme and thus cause a pseudo-MTHFR deficiency. 

Are we getting too much folic acid in the USA? I've come across articles about north American study populations that found unmetabolized folic acid in 40-95% of fasting study participants. (http://ajcn.nutrition.org/content/92/2/383.longhttp://jn.nutrition.org/content/145/3/520.short) From that, I conclude that many in north America are definitely getting more folic acid than they need.

Am I anti-folate? Not at all. Every woman should take measures to ingest enough folate if she thinks she could become pregnant in order to lessen the risk of neural tube disorders such as spina bifida. But I think folic acid is a terrible form of folate to be putting in everyone's food and multivitamins. Folate is available in many foods naturally and in other supplement forms, including actual 5-MTHF.

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Wednesday, March 29, 2017

It's time to end the autism epidemic (part 1)

Two weeks ago, a group of researchers published their findings about biological markers that can be used to a high degree of accuracy to predict the presence or absence of autism. In other words, they have deduced and tested a highly accurate "blood test" for autism. Here is the link to the entire report: http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1005385.

Here is the abstract:

The number of diagnosed cases of Autism Spectrum Disorders (ASD) has increased dramatically over the last four decades; however, there is still considerable debate regarding the underlying pathophysiology of ASD. This lack of biological knowledge restricts diagnoses to be made based on behavioral observations and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets.

Here is a pictorial summary of folate-dependent one-carbon metabolism:


http://journal.frontiersin.org/article/10.3389/fgene.2011.00036/full
And here is an illustration of the transsulfuration pathway:

https://www.researchgate.net/figure/261328951_fig2_The-methionine-cycle-and-transsulfuration-pathwayNotes-Glutathione-synthesis-begins
Do you see where the two connect? It's at the part where methionine is converted in steps to homocysteine and then the homocysteine is recycled to methionine. The major homocysteine-to-methionine pathway is via the enzyme methionine synthase (MS).

In 2013, preliminary findings (due to the small study size) were reported that clearly indicated prematurely low levels of methionine synthase mRNA in autistic subjects' brains during their early years. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577685/) I highly recommend viewing the findings as graphically represented (here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577685/figure/pone-0056927-g005/) as they make it clear just how dramatic the difference is during crucial years in child development.

Why is the methionine-homocysteine cycle important in autism? Autism spectrum disorders are pervasive developmental disorders that are characterized by delays in multiple areas of development, and candidate genes for autism seem to constitute an ever-lengthening list. An influential theory currently is that epigenetic mechanisms are involved, particularly DNA methylation (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955092/), which ties directly into the s-adenosylmethionine (AdoMet or SAMe) made from methionine (as illustrated above).

If a methionine synthase transcription deficiency can cause autism via epigenetic mechanisms, that suggests we need to efficiently and vigorously support the activity of whatever MS-associated activity is present. That is where getting the proper forms of folate and cobalamin (B12) comes in. I'll go more into detail on that tomorrow.

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Tuesday, March 28, 2017

It's time to end the autism epidemic (Introduction)

The evidence in the past few years continues to accrue, pointing to a defect in the methionine synthase homocysteine-to-methionine pathway as being behind the development of autism. In the next few days, I will lay out the evidence for how we address that problem and probably end the human-caused autism "epidemic" of the past couple decades.

1) Proper support of the methione synthase pathway requires having the right kinds of folate and cobalamin. In the pursuit of cheap and stable vitamin supplements, we have made a mistake using cyanocobalamin and folic acid. Those should be phased out in multivitamins and fortified foods as soon as possible and replaced with other, more appropriate forms of B12 and folate.

2) Glycine betaine should be a standard part of multivitamin formulations. It supports the betaine-homocysteine S-methyltransferase (BHMT) minor homocysteine-to-methionine pathway. The best way to get glycine betaine in the diet appears to be via ingestion of the water used in boiling beetroot and spinach, which is supported by the low autism rates found in places where such liquid is commonly included in regional cuisines, such as Poland (barszcz czerwony) and the Punjabi region (saag or palak puree).

I cannot emphasize strongly enough how disappointed and heartsick I am that modern medicine and health initiatives have, due to cost considerations, led to heavy mass usage of inferior forms of B12 and folate and consequently inflicted pervasive developmental disorders on so many children, including one of my own relatives. I love science, medicine, public health initiatives, proper vitamin use, and capitalism. Something went seriously awry in public health policy in many countries, and it's time to fix it.

**This is one of a series of posts. Here are the links to each entry in the series.**

Introduction
Part 1
Part 2
Part 3
Part 4
Conclusion

Saturday, March 25, 2017

Addressing one anti-vaccine alarmist

I have a family member I consider very intelligent, except on one point. She has bought into the "vaccines are a bigger risk than benefit" idea and promotes that persistently. She has two personal reasons for being set against vaccination, at least here in the USA where the risks are certainly lower for contracting polio than in, say, Syria. They are:

  1. Years ago, her neighbor lost a baby to sudden infant death syndrome (SIDS) right after the child was vaccinated.
  2. She did get a vaccination for her oldest child, and he had a febrile seizure afterward, which she blames on the vaccination.

I'll address each point.

1) Any SIDS death is tragic and too often unexplained. However, research statistics indicate that SIDS risk is neither increased nor decreased by vaccination. (https://www.ncbi.nlm.nih.gov/pubmed/22289512) SIDS appears correlated with breathing difficulties, particularly those related to mild upper respiratory infections and cigarette smoke (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1619535/?page=1https://www.nichd.nih.gov/sts/campaign/science/Pages/causes.aspx). Per the CDC, upper respiratory infections are not common side effects of any childhood vaccinations:
https://www.cdc.gov/vaccines/vac-gen/side-effects.htm.
Do you know what apparently can be a good source of upper respiratory infections? Going to the pediatrician's office, where there is a good chance of finding rhinovirus-shedding children. (http://www.today.com/moms/taking-your-healthy-kids-doctor-may-make-them-sick-2D12110565, https://www.ncbi.nlm.nih.gov/pubmed/20135827) Thus, regardless of vaccination, simply having gone to the pediatrician recently might conceivably have increased the chance of SIDS for my relative's neighbor's child.

2) A febrile seizure is associated with having a fever. ("Febrile" means having a fever.) Febrile seizures are relatively common, affecting up to 6.7% of children. (https://www.ncbi.nlm.nih.gov/pubmed/16510738) The fever after an immunization is a result of an immune response to the partial, weakened, or dead bacteria or viruses in the vaccine. Fever is a common side effect of nearly every available vaccine. (https://www.cdc.gov/vaccines/vac-gen/side-effects.htm). That is because fevers are part of a functioning immune system, and moderate fevers help save our lives when fighting infections. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786079/) Febrile seizures are more likely right after vaccinations (although not delaying vaccinations in toddlers results in a lower risk of febrile seizures: http://pediatrics.aappublications.org/content/pediatrics/early/2014/05/14/peds.2013-3429.full.pdf), but getting the vaccine-preventable illness is far more likely to result in febrile seizures if H1N1 is representative of what happens with infections generally. (https://www.ncbi.nlm.nih.gov/pubmed/26073015https://www.ncbi.nlm.nih.gov/pubmed/26553258) If one is certain that children will never encounter a vaccine-preventable illness, it is rational to not get the vaccine. But when is something like that certain? If one is wrong, and the child's immune system has to fight off the illness, there will likely be worse consequences--including febrile seizures--than the child would have suffered from the vaccine.

So is my relative right to treat vaccines as something she should avoid? Well, not with respect to the SIDS argument. But avoiding immunizations for her children probably has decreased the incidence of fevers and febrile seizures for her children, for she keeps a clean house and they haven't come down with measles, mumps, rubella, polio, etc. Their not having come down with vaccine-preventable diseases, however, is a result of her living in the USA, her own caution, and good luck. Next week a recently arrived traveler from Chicago could bring mumps to a school in her area, and her sons could end up with meningitis or decreased fertility as a result. I don't think her risk-benefit analysis has led her to the best decision for her family because she is unaware of how easily vaccine-preventable diseases can be brought to her orderly doorstep.

Wednesday, March 22, 2017

Silent, but not deadly

Today's topic is flatulence. Everyone passes gas. The trick is to have no one notice when it happens, which requires both silence and an absence of noticeable odor. Where does the offensive odor come from? Sulfur! Yes, brimstone (an archaic word for sulfur) really does deserve to be associated with imagined conceptions of hell. Specifically, hydrogen sulfide (H2S) correlates with the level of stinkiness of flatulence. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727181/)

Happily, we know how to bind H2S. Bismuth, zinc, iron, and nitrate are able to do so. (https://www.ncbi.nlm.nih.gov/pubmed/12927694) Nitrate is considered toxic, but the other three are commonly ingested by people. Bismuth is in Pepto-Bismol, and zinc and iron are in many foods and taken as vitamin supplements. Treatment with bismuth has been proven to bind fecal H2S in humans (http://www.gastrojournal.org/article/S0016-5085(98)70311-7/fulltext), but long-term supplementation with bismuth is possibly connected to encephalopathy; brain dysfunction is too high a price for me to pay to get rid of bad-smelling flatulence, so I won't run out and buy myself a bottle of Pepto-Bismol for that purpose. But zinc...that's in common use as a supplement, especially in connection with fighting colds, and appears relatively safe as long as one keeps zinc intake below 40 mg in a day. (https://umm.edu/health/medical/altmed/supplement/zinc) Moreover, the body has no specialized zinc storage system. People occasionally eat oysters, which are extremely high in zinc, and don't appear to be negatively affected by eating the oysters. Zinc is worth a try.

My husband's digestive system doesn't handle onions well. I was sad as a newlywed to realize that onions were going to have to be cut out of the household menu for his sake. And over time my gut bacteria seem to have altered so that I also have a hard time with onions now. This was a very unfortunate change to a woman who loves salsa. But then two days ago, I discovered from the studies cited above that H2S can be bound with easily obtained minerals, and so we experimented. Last night for dinner, we ate a packaged, reconstituted potato and onion soup that gave us both extraordinarily unpleasant gas about a year after our marriage. We adults took some chelated zinc right before eating the soup. We both had some gas today, but it didn't stink. Hurrah! We are fairly confident that the zinc helped us because our seven-year-old, who didn't get any zinc and did eat two bowls of the soup, had decidedly malodorous gas this morning.

Next step: Mexican food (well, American-style "Mexican" food, which really isn't the same thing as authentic Mexican food) with some zinc in our accompanying beverage. I really hope this works so that I can go back to cooking with onions.

Thursday, March 16, 2017

Natural remedies over the millennia

A promising trend I see on PubMed recently is a swelling of interest in and scientific research on natural compounds from herbs and foods that have been used by humans for thousands of years. There is relatively little profit motive for pharmaceutical companies to fund such research, so it has been neglected. There's certainly a need for new, patentable molecules designed to selectively inhibit certain processes in the body and to correct for genetic faults, but we have a lot of naturally occurring molecules to investigate, as well.

LDS people (Mormons) have scriptures that say

"And again, verily I say unto you, all wholesome herbs God hath ordained for the constitution, nature, and use of man— Every herb in the season thereof, and every fruit in the season thereof; all these to be used with prudence and thanksgiving.

But which herbs are wholesome? And for what conditions? Despite attempts to keep track of herbs and their effects for the past 5000 years, if Chinese oral tradition is accurate, humanity still has a long way to go in figuring them out.

Only 5000 years did I say? It looks like the Neanderthals might have been using natural remedies to treat their physical ailments well over 40,000 years ago:

"One of the most surprising finds, however, was in a Neanderthal from El Sidrón, who suffered from a dental abscess visible on the jawbone. The plaque showed that he also had an intestinal parasite that causes acute diarrhoea, so clearly he was quite sick. He was eating poplar, which contains the pain killer salicylic acid (the active ingredient of aspirin), and we could also detect a natural antibiotic mould (Penicillium) not seen in the other specimens.""Apparently, Neanderthals possessed a good knowledge of medicinal plants and their various anti-inflammatory and pain-relieving properties, and seem to be self-medicating. The use of antibiotics would be very surprising, as this is more than 40,000 years before we developed penicillin. Certainly our findings contrast markedly with the rather simplistic view of our ancient relatives in popular imagination."
http://popular-archaeology.com/issue/winter-2017/article/dental-plaque-dna-opens-new-window-on-neanderthal-life-ways

Reading that makes me think we should routinely reevaluate all the traditional remedies and "old wives' tales" to see whether new research has found out something indicating whether and how there might be something to those old uses of plants and other natural substances. (While we're at it, we should also probably stop maligning Neanderthals as stupid nonhumans if they were using penicillin intentionally that long ago.) Giving barley water a fresh look helped me see how molybdenum can help with migraines and nausea. Who knows what other real natural remedies we modern humans are missing?

Monday, February 27, 2017

"That which cometh out of the mouth"

I have another new theory. No, it's not exactly received medical wisdom. That's what makes it new. :D

In the past few days, I've learned a lot about how atherosclerosis (plaques building up on artery walls) can lead to stroke. I had previously hazily envisioned strokes being caused by a blood clot that just magically appeared in the brain. To the contrary, the blood clot generally comes from somewhere besides the brain. Typically, an atherosclerosis-related stroke-causing blood clot originates in the carotid arteries, right at the point where the carotid artery divides into two arteries, the internal carotid artery and the external carotid artery. Atherosclerotic plaques build up in the vicinity of that "Y"-shaped fork, and rupturing of the plaques triggers formation of a blood clot which then moves up into the head and gets stuck in a smaller artery in the brain.

What causes plaques in the first place? An influential theory is that oxidized LDL cholesterol starts the process of atherosclerosis. (https://academic.oup.com/cardiovascres/article/68/3/353/309912/Oxidized-LDL-a-critical-factor-in-atherogenesis) My questions then are 1) how does the LDL get oxidized and 2) why does it cause plaques right at that carotid junction?

First I looked into what causes the oxidization. A major culprit behind oxidizing of LDL is hypochlorous acid produced by the enzyme myeloperoxidase, which uses hydrogen peroxide (H2O2) and a chloride ion (Cl-) to do so. (https://link.springer.com/article/10.1007/s12170-013-0291-3, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315351/, http://onlinelibrary.wiley.com/doi/10.1002/biof.5520060208/abstract, http://atvb.ahajournals.org/content/20/7/1716.long?related-urls=yesl20/7/1716)

H2O2 is supposed to be broken down in our bodies by catalase, glutathione peroxidase, and peroxiredoxins. Glutathione peroxidase activity appears to decrease as we age. (https://www.ncbi.nlm.nih.gov/pubmed/18511755) It's not clear exactly why, but our ability to break down H2O2 with our saliva appears to go down by approximately half as we age (https://academic.oup.com/biomedgerontology/article/62/4/361/629357/Age-Related-Changes-in-Salivary-Antioxidant), which means that there is likely going to be some extra H2O2 in our mouths in our later years. Excess H2O2 is harmful to gum tissue (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730038/), and in the gum tissue H2O2 can apparently diffuse in such a way as to end up in the jugular vein (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745256/).

The jugular vein travels down through the neck, taking all the "used" blood from the head back to the heart. In the neck, the jugular vein is covered by the carotid sheath, which holds the jugular vein next to the carotid artery. My novel hypothesis is this:

Excess aging-related H2O2 from the mouth goes into the jugular vein and then makes its way over to the carotid artery next door, boosting the amount of oxidized LDL in the carotid artery just before it hits the "Y"-shaped fork, where the oxidized LDL hits the sides of the branching arteries and starts the process of forming atherosclerotic plaques. 

I think the weakest link in my theory is that I can't find a lot of clear proof that H2O2 can migrate from a vein into a neighboring artery; however, it does seem to be generally accepted that H2O2 diffuses through tissues:

It is now widely accepted that this low molecular weight molecule is utilized in metabolic regulation in ways similar to diffusible gases such as NO, CO, or H2S. Even more so, H2O2 is recognized as being in the forefront of transcription-independent signals, in one line with Ca2+ and ATP. H2O2 diffuses through tissues to initiate immediate cellular effects, such as cell shape changes, the formation of functional actomyosin structures, and the recruitment of immune cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979367/

I suppose this will have to suffice for now. It's time to go eat dinner with my family...a nice, low-fat, high-soluble-fiber, and antioxidant-full meal.

(I almost forgot to explain the title of my post. In Matthew 15:11, it is recorded that Jesus said, "Not that which goeth into the mouth defileth a man; but that which cometh out of the mouth, this defileth a man." My research above points to oxidizing substances from the mouth contributing to the formation of atherosclerotic plaques in the carotid arteries.)

Friday, February 24, 2017

Possible transient ischemic attack

My husband, who is barely "middle-aged," experienced something on Tuesday that appears to have been a transient ischemic stroke (TIA), which is considered a warning mini-stroke. He'll be getting a possible-TIA workup done at the hospital in the next few weeks, and he has begun taking a baby aspirin daily.

This is a man who is at a healthy weight and who cycles about 25 miles per week. He doesn't smoke, drink alcohol, or use drugs. He is, however, cursed genetically (his grandfather died at age 45 of an enlarged heart) and likes desserts and fast food pizza too much.

The episode happened within 24 hours of a daughter's birthday party, which featured triple meat pizza from Little Caesar's, birthday cake made with lots of butter, and ice cream. And we think he had an egg for breakfast the following morning. He has had high cholesterol and triglycerides for years, but he had hoped to stay healthy by dint of lots of exercise and fruits and vegetables. It looks as though he'll also have to largely cut out some favorite treats, too, though. :(

On the bright side, he did escape the illness I posted about last time.

Wednesday, February 15, 2017

H1N1?

Over the past five days, 6/7 family members have been struck with a cold or flu virus. Because it started with an intense sore throat for me, I thought it might be strep throat, but the tell-tale symptoms in the throat never showed up. What was weird was that instead of a bunch of coughing and sneezing initially, it started with a day of fatigue just lying in bed with no/little hunger. I found out last night that friends from our church congregation have confirmed H1N1 ("swine") flu. I compared H1N1 symptoms with the symptoms we have, and they seem to be a pretty good fit.

So life is on hold for us while everyone rests. Except for Daddy, who insists he'll escape it, we're self-quarantined at home. The heat is turned up, and the air humidifier is turned up. I'm also taking a lot of melatonin to see if it helps shorten the course of the illness. I felt better yesterday, so I stayed up to my normal time (past 11 pm). I ended up regretting that, so I don't think just taking melatonin is an adequate substitute for insufficient rest. The evidence I found last year did only point to melatonin being possibly helpful for avoiding ARDS (acute respiratory distress syndrome), and I have to admit, my lungs seem to be doing OK. So maybe there's merit still to my hypothesis, but right now I'm dissatisfied with anything that doesn't make me feel better immediately.

Friday, February 10, 2017

A definition with a difference

I don't care to get political on my blog for the most part. I'm bending my usual course today for a very good legal reason, which I'll lay out below.

On January 27, President Trump signed an executive order temporarily staying entry under the Immigration and Nationality Act (INA) for aliens (i.e., non-citizens and non-nationals of the USA) from countries previously identified as being of higher risk due to harboring/sponsoring of terrorists. Here's the relevant paragraph:

    (c)  To temporarily reduce investigative burdens on relevant agencies during the review period described in subsection (a) of this section, to ensure the proper review and maximum utilization of available resources for the screening of foreign nationals, and to ensure that adequate standards are established to prevent infiltration by foreign terrorists or criminals, pursuant to section 212(f) of the INA, 8 U.S.C. 1182(f), I hereby proclaim that the immigrant and nonimmigrant entry into the United States of aliens from countries referred to in section 217(a)(12) of the INA, 8 U.S.C. 1187(a)(12), would be detrimental to the interests of the United States, and I hereby suspend entry into the United States, as immigrants and nonimmigrants, of such persons for 90 days from the date of this order (excluding those foreign nationals traveling on diplomatic visas, North Atlantic Treaty Organization visas, C-2 visas for travel to the United Nations, and G-1, G-2, G-3, and G-4 visas).

The following day, a DHS spokesperson emailed a journalist that the order would bar green card holders (i.e., legal permanent residents or LPRs; the residency cards haven't been green for decades), which of course set off a panic with all the LPRs who rightfully thought they were done dealing with immigration roadblocks. So the following day, DHS said that it was in the national interest to use the flexibility of the order to not bar LPRs. What did DHS miss in all this? The definitions section of the INA specifically exempts LPRs from needing "admission" (which includes "entry" authorized by an immigration officer) under the immigration laws unless they've done something to lose their LPR status. Here's the relevant statute:

  INA Section 101(13)     (A) The terms "admission" and "admitted" mean, with respect to an alien, the lawful entry of the alien into the United States after inspection and authorization by an immigration officer.          (C) An alien lawfully admitted for permanent residence in the United States shall not be regarded as seeking an admission into the United States for purposes of the immigration laws unless the alien-[and then there is a short list of things saying what an LPR can have done to lose LPR status, which is primarily commit a crime or overstay outside the USA].  

An LPR is considered already "admitted for permanent residence." They don't have to "enter" the USA under the umbrella of the immigration laws. Which makes sense because they already immigrated. Immigrate is a verb meaning to move to a place to settle down, and once you've done it, you don't have to do it again, so no more messing around with immigrant petitions, immigrant visas, or immigrant admission. LPRs are simply coming home when they return back to the USA after a short stay abroad. Hence the executive order doesn't do anything to bar LPRs because they require no "immigration benefits" to reenter the USA once inspection reveals that they are indeed LPRs who remain in status.

Why am I talking about all this now? Because no one, from DHS to the White House counsel to the DOJ to the Ninth Circuit Court of Apppeals seems to have caught this point of law. Yesterday's ruling from the Ninth Circuit openly and clearly makes this mistake, as seen on page 20 of its ruling:

In the district court, the States argued that the Executive Order violates the procedural due process rights of various aliens in at least three independent ways. First, section 3(c) denies re-entry to certain lawful permanent residents and non-immigrant visaholders without constitutionally sufficient notice and an opportunity to respond. Second, section 3(c) prohibits certain lawful permanent residents and non-immigrant visaholders from exercising their separate and independent constitutionally protected liberty interests in travelling abroad and thereafter re-entering the United States. 

Do you see what the Ninth Circuit did there? They interpreted "immigrants" from the executive order to mean LPRs. This is a dumb mistake showing that of all the lawyers involved no one, even at the penultimately-supreme court level, has looked at INA Section 101 and realized that LPRs aren't treated by the law "as immigrants" when it comes to entering the USA. Any DHS agent working a port of entry knows that LPRs aren't the same thing as someone entering the USA with an immigrant visa in hand; the first category already did immigration paperwork in the past (huge hassle that it all was for them) at the border and/or in the USA, while the second is currently immigrating and has to be "processed" as an "immigrant" in "secondary." The executive order couldn't deny immigration benefits to LPRs entering the USA because they don't need immigration benefits to enter.

I know the INA is tricky, but this mistake should never happened. Every lawyer in the executive branch and courts who let this through should be embarrassed that they didn't check the INA definitions.