As you know, in Functional Medicine we assess and treat chronic illness by looking at antecedents of illness, triggers of illness, and mediators of illness (things that maintain dysfunction). We consider the systems (digestion, nutrition, immune/inflammatory/infectious, detoxification & biotransformation, oxidative stress/mitochondrial function, endocrine function, genetics, epigenetics, and lifestyle and psychosocial factors) which, when dysregulated, cause disease. We then test suspected systems and determine a personalized treatment plan based on the whole picture (symptoms, signs, history and lab data).
In addition to this functional medicine approach, we now have the advanced capability to look at what is happening inside the brain at functional nerve tracts, networks, as well as the surface of the brain, using the quantitative electro-encephalogram (qEEG). Normally, I would have done a qEEG already, but this was delayed due to COVID-19. I suggest that we run a qEEG to determine what is going on inside the brain. This will enable us to intervene in additional ways to enhance your brain function. By assessing and treating the terrain (the functional medicine systems described above) and treating the brain directly (based on the qEEG data), we can effectuate much greater recovery than functional medicine alone.
In preparation for writing your plan I had a long conversation with Dr. S. and his explanation was completely consistent with my understanding of your of abrupt withdrawal from Xanax, and what to do about it. We are in agreement on the approach in regards to your GABA receptors. Dr. S. believes that you should coordinate all of your neuro-psychiatric care under my umbrella, and that includes the psychopharmacology.
What follows is a personalized and highly specific plan developed for you, based on the history, physical exam, and laboratory data, and review of records.
Overview of the abnormal findings:
The Terrain: Functional Medicine
Findings:
1. Thrombocytopenia: Low levels of platelets as well as an increased red blood cell count suggests to me that you should have a consultation with a hematologist. Nutritional deficiencies, viral infections, toxins, medications and immune system problems are among the many potential causes of low platelets. While I think it is unlikely that there is anything serious going on, in the setting of high numbers of red blood cells, probable splenomegaly (August 2017, Diagnostic Imaging Services Virginia Hospital Center), and a drop in the platelets, a thorough evaluation with the hematologist is in order, to be on the safe side. At that same time (August 2017) there was concern that you may have had discitis/osteomyelitis. I don’t know how that was resolved but sometimes chronic infection could cause some of these hematologic abnormalities. This should be investigated thoroughly. Please do the pulse oximetry test I recommended at our last meeting since chronic hypoxia can also cause thrombocytopenia.
2. Herpes Virus type 6: This virus can cause cognitive and emotional problems; The treatments available are intravenous. You will need a consultation with an infectious disease specialist, who will do more testing; In some cases the HHV-6 is inherited and is part of the genome, and in other cases (most) it is acquired. Sometimes, the doctor will want to take some spinal fluid. We should have the qEEG done BEFORE you see the infectious disease doctor. Some of the treatments can suppress the bone marrow, therefore the cause of the thrombocytopenia (low platelets) needs to be assessed first. Another option is, since your cortisol is so low, to treat the low cortisol with physiologic doses of hydrocortisone (bio-identical hormone, which will help you manage stress) and see if it allows your immune system to push the HHV6 into remission. The risk is that high doses of steroids can sometimes increase viral replication. We can discuss this.
3. Generalized Neurological (Central and peripheral) dysfunction: Traditional medicine would diagnose two separate issues: chronic encephalopathy, and peripheral neuropathy. The computerized test which you did, CNS vital signs, showed a significant scatter of results. This indicates a generalized brain dysfunction. The neurological testing you had done in January 2017 and April 2019 demonstrate a sensory motor neuropathy that is bilateral. Fact that it is bilateral indicates a generalized process. This could be due to a disc problem, and, or metabolic issues as outlined below. Putting this together it is clear that your nervous system whether inside your brain or in the body is under high levels of stress from the processes outlined below.
4. Metabolic Issues:
a. You have high levels of oxalates which can be a significant contributor to pain/fibromyalgia as well as a risk factor for kidney stones, which you have had in the past. Based on the organic acids test it is suggestive that there is a genetic basis for this. At this point I suggest that you go on a low oxalate diet for one month and assess any benefits that you see in pain. Additionally you can use calcium citrate 1000 mg before meals that are high in oxalates but I would not use that strategy during this month. Nutritional support can help reduce this problem, and increasing your bile acids to allow you to absorb fat and therefore fewer oxalates, can also help this problem.
b. Pyrolluria: Measurement of urinary pyrolles indicates high levels (you are 15.65—normal <10). The result of this is altered heme production (heme is made of an iron molecule bound to a porphyrin ring), which is required for normal neuronal function. Pyrolles bind to B6, and zinc, reducing availability for the body. The brain relies on zinc more than any other organ, and your zinc is somewhat low. Biotin, and magnesium levels can be affected as well. Additionally, GABA and serotonin function are reduced. The reduction in available B6 means that you have less buffering capacity for excessive amounts of aldehydes (see toxins below).
c. Sulfur metabolism: Genetic analysis (see report) indicates you may be having trouble with sulfur containing compounds, and this affects your ability to detoxify substances. (SUOX: 8/10 of the genes are variants); A bottleneck here would impair the function of sulfite oxidase, preventing complete breakdown of sulfur-containing amino acids. Methionine, cysteine, homocysteine, and taurine are the 4 common sulfur-containing amino acids. Homocysteine is high giving a high sulfur burden. As result, sulfites and other compounds left over from the partial breakdown of sulfur containing amino acids, or foods (e.g., garlic) abnormally accumulate in the body. Researchers suggest that the nervous system is especially sensitive to this abnormal accumulation, and excessive levels of sulfite compounds are toxic to the brain. This gene requires Molybdenum. We should start this right away.
5. Gastrointestinal function:
a. Multiple food allergies-this is relevant to your cognitive and emotional experience as the inflammation from the gut actually is transmitted to the brain through four or five different pathways. The result of this is lower levels of GABA, and higher levels of glutamate, which causes increased levels of anxiety. In addition, this reduces the ability to make serotonin for mood regulation. Finally, the level of inflammation in your gut uses zinc which then depletes your brain of zinc. Zinc is necessary for normal serotonergic neurotransmission. The brain uses more zinc than any other organ in the body unless the immune system is activated as in infection or gastrointestinal problems. Treating your gastrointestinal tract will actually help reduce your anxiety and calm your mind.
b. Poor fat absorption-your absorption of fat is low and this affects both the increase in oxalate absorption as well as affecting the brain since most of the brain is actually composed of fat. Neurotransmission in the brain occurs in part via myelin and adequate fats of the appropriate types need to be absorbed. This does not appear to be a pancreatic problem but rather the production of bile acids is likely low.
c. High levels of immune activation in the gut (secretory IgA is 1429 (nl<885) indicating inflammation.
d. High levels of a pathogenic bacteria called klebsiella. We will treat this using various plant compounds, an antifungal which is not absorbed, a digestive enzyme, probiotics, and finally an antibiotic. This will reduce the inflammation in your gut and overtime reduce the inflammation in the brain, and the food sensitivities.
6. Nutrition:
As a result of the gastrointestinal problem, and perhaps your diet there are numerous nutritional deficiencies many if not all of which affect your nervous system and could be responsible and significant degree for your neuropathy, and some of your cognitive emotional difficulties. I will make a supplement that contains many of these nutrients although some will be given to you separately, and overtime once the gut is healed the need for these additional nutrients will diminish significantly.
7. Mitochondria:
The mitochondria are the power houses of the cell. They produce ATP, the energy molecule that allows all biological function to occur. Your brain is demanding higher than usual amounts of energy (see above), however your mitochondria are demonstrating an area of difficulty.
a. The levels of isocitrate are high normal (65, normal 22-65), and the next molecule in the energy production chain is low normal range (alpha-keto-glutarate = 10, normal is 4-52). This means that there is some partial blockage in the ability to meet higher than normal energy demands you are under; The blockage is due to genetics, B3 deficiency, magnesium or manganese deficiency, or a combination of those.
b. Reduced Beta-Oxidation of fats: The mitochondria use glucose for fuel, but also can use fats in a process called beta-oxidation. In two different tests, from two labs, you show impaired beta oxidation. This could also have genetic or nutritional causes (carnitine or B2 deficiency). People with impaired beta oxidation usually complain of fatigue and lethargy.
8. Hormones:
a. Adrenal hormones are dysregulated. The ‘HPA adrenal hormonal axis’ (the axis has 5 parts to it: the prefrontal cortex (not functioning properly for you right now), the hypothalamus, the pituitary (overworking a bit with higher than normal ACTH hormone), the adrenal glands (not responding well to the ACTH most of the day until late afternoon or evening), and the cellular nuclear receptors (genes, such as NR3C1/FKBP5/CRHR1/2, CRHBP). Abnormalities in the HPA Axis result in reduced cognitive function, depression, increased risk for PTSD, light-headedness on standing, inability to cope with stress, and immune problems. The cortisol levels are low or low normal, and consistent with chronic stress the levels of DHEA are very low; The pregnenolone level (pregnenolone is the ‘mother’ of all adrenal hormones and is made from cholesterol) was quite low. The genetics indicate that the source of this problem is very likely the NR3C one gene. You have many variances in that gene. This increases your risk for PTSD, light-headedness on standing, inability to cope with stress, and immune problems. This is relatively straightforward to treat however I cannot be aggressive with this until the question of the herpes virus is resolved. Using low-dose bio identical steroids is very effective however it can cause increase multiplication of the herpes virus so we will have to wait on this treatment. There are other treatments that we can do and these are in the plan and they are affective but take a longer period to work.
b. Melatonin levels are low normal; Since this is a brain protector and anti-oxidant as well as sleep regulator, we will give you a low dose every evening at the same time. Hormones are best used at the same time each day as they synch and work best with the light/dark cycle. It is likely that these levels are low in part due to the genetics which affect your ability to make serotonin. Melatonin is it self derived from serotonin. In addition when there is more inflammation in the body such as from your gut, less serotonin is made and therefore less melatonin is made. This obviously affects the brain as well as sleep.
c. DHEA: your levels of DHEA/DHEA sulfate were subnormal. We have replaced that and you re-tested and were found to be in a normal range. Pregnenolone was supposed to be tested but was not therefore I have a requisition to do that.
d. Thyroid: your thyroid numbers are normal. My concern is that your genetics indicate that you do not make adequate amounts of T3 in the brain. This increases the risk for depression and treatment with hyper metabolic doses of T3 actually has been shown to be very helpful in mitigating depression and improving Cognition. I cannot treat this until the adrenal problem is addressed as you would not tolerate it. The adrenal problem as discussed above.
9. Methylation:
Levels of folate metabolites (making neurotransmitters etc.) are low, and levels of SAH are high; High SAH inhibits methylation reactions affecting neurotransmitters; This will normalize over time (9-18 months) as we treat the gut, and provide you some folates. Overall your methylation panel looks better than most.
10. Toxins:
a. Mold: You have elevated levels of Ochratoxin A (682, normal, < 7.5). This is neurotoxic and the levels are high. This is consistent with the type of mold found on your ERMI report. There is some evidence in animals that Ochratoxin A can cause DNA damage in the spleen liver and kidneys of mice. If you can remove yourself from the environment immediately that would be ideal. If not you should purchase an iAdapt AirOasis filter for the major living areas ASAP.
b. Organo toxins: you have elevated levels of eight different Organo-toxins. Four of these, numbers one for 12 and 15 affect the nervous system. Number 16 is a hormone disruptor. Number two can affect coagulation. Toxin # 4 (styrene) was identified across three different platforms (e.g., mandelic acid=0.79, normal < 0.09), and affects mitochondrial function. You need to do your best to determine the sources of these, and we will work to support and improve your liver detoxification function and clean your air. In addition when you are ready we will increase detoxification by increasing your sweat production as to some degree toxins are excreted in the sweat. This is a moderate level of toxins, and importantly we do not know how they interact with each other and with one’s genome. Part of your long-term health goal will be to reduce these toxins.
11. Immune/Inflammation:
a. Most of your immune markers were completely normal, and importantly you are not making any antibodies against brain proteins. This is obviously very good. Your levels of complement factor 4a (C4a) is somewhat elevated indicative of inflammation. Additionally, your CRP (C-reactive protein) has come down from 3.8 to 1.73 over the last several months. This is a good sign I would like to see it under 1.0.
b. The nasal culture indicated that you have bacteria in your nose that are creating a significant amount of biofilm and contributing to inflammation. These bacteria can be easily treated with colloidal silver. Clearly using our air filters and removing the mold will be helpful as well. Finally the bacteria are indeed sensitive to tetracycline which is going to be used to treat the klebsiella in your gut so we will be able to hit two birds with one stone.
12: Genetics: there are five main areas of concern
a. The hormones seem to be affected by genes that are affecting both your adrenal and thyroid function. These are NR3C1 and DIO2. DIO2 (makes T3 in the brain): 4/8 are variants: This indicates the potential benefit of using supraphysiologic doses of thyroid hormone. Your genetics (and your symptoms) suggest that your brain, due to these variants, is not making enough free T3. This is needed for proper serotonin receptor function, proper beta-adrenergic function (e.g. alertness), and in your body (DIO1) where you also have variants, with proper immune function.
b. Neurotransmitters: do you have significant difficulty making serotonin with 11 of the 16 genes under functioning. Additionally your dopamine beta hydroxylase function is diminished reducing your ability to make nor epinephrine from dopamine. This would affect concentration. In part this is offset by COMT genetic variants which allow you to accumulate higher levels of neurotransmitters.
c. Progesterone receptor: 15/20 of your genes are variants. Progesterone has a GABA-ergic action. There is very little information on the use of progesterone in males, although it is clear that progesterone, in men and women, has effects on most cells. Options: Very low dose progesterone (experimental); higher doses of Riboflavin, and niacinamide (Niacinamide will be in your Village Green Compound). Although estrogen and progesterone are gonadal steroid hormones, their actions are not restricted to reproductive organs and functions. Estrogen and progesterone exert effects on various organs systems including the central and peripheral nervous systems, and they play a significant role in growth and development. In the past three decades, there has been increasing evidence that estrogen and progesterone are neuroactive hormones. In recent years there has been a growing body of clinical evidence that has demonstrated neuroprotective effects of estrogen and progesterone. Studies have further proposed that estrogen and progesterone serve as general neurotrophic molecules that stabilize neuronal function, support neuronal viability, and, under certain conditions, prevent neuronal death. Interestingly, epidemiological studies have observed gender differences in the incidence of a wide range of unrelated neurological and psychiatric disorders, and it has been suggested that estrogen and progesterone among other factors contribute to this difference [5]. The mechanisms of these neuroprotective effects, however, are poorly understood. The purpose here is to review both the preclinical and clinical literature that demonstrates the neuroprotective
(Brotfain E, Gruenbaum SE, Boyko M, Kutz R, Zlotnik A, Klein M. Neuroprotection by Estrogen and Progesterone in Traumatic Brain Injury and Spinal Cord Injury. Curr Neuropharmacol. 2016;14(6):641–653. doi:10.2174/1570159×14666160309123554)
d. Sulfur metabolism (See above)
e. NOS3-8/12 genes are variants. This leads to inadequate production of nitric oxide. Nitric Oxide is a signaling molecule between neurons (positive feedback, neuroplasticity), and also helps with vasodilation, and blood flow via relaxation of the endothelium. Outside of the vascular system, NO participates in the immune response to infection. Your levels of L-Arginine, needed to make NO, are subnormal. Arginine comes from citrulline. Your citrulline is high. Molybdenum-1mg-Thorne Brand -P5P-per directions on the plan-Betaine HCL-Piping Rock Brand (400mg) in the middle of each meal-Avoid Omega 6’s (Evening Primrose) -Continue hydroxycobalamin
In summary: Your nervous system is under siege. Many of the processes outlined above were probably in place for several years, and some of the processes are genetic in origin. However, with the sepsis three or four years ago and the stress of the rapid Xanax taper, the dysfunctions were accelerated.
If you follow my plan closely, we can very substantially and significantly correct these problems so that you will have a significant restoration of function (using the modalities below), however the viral (herpes) issue and the source of the low platelets (i.e., is it an enlarged spleen or is it due a bone marrow issue) needs to be resolved so we can move ahead fully. I do want to emphasize that you do need to follow my plan and all the recommendations we agree to each meeting very closely. I have great success treating people who adhere to the plan closely.
Robert Hedaya, MD, DLFAPA, ABPN, IFMCP
Follow up Testing
Please do the following tests:
· qEEG
· LabCorp tests
· Parasitology testing at parawellnessresearch.org
· Pulse Oximetry
· Urine toxic Elements test
General Instructions
1. Add the items in the chart below as close to the order in which they are listed as possible.
2. Register with Valisure.com to get medications -they check each batch for potency and some contaminants.
3. All supplements are taken in the middle of meals unless otherwise instructed.
4. I can place most of the supplements on a central Fullscript website (easy ordering) where you will get a discount. Let me know if you would like this to be done. Once you know you are tolerating a supplement, you can eventually order a few bottles at a time.
5. Get a vitamin pill organizer with breakfast, lunch, dinner bedtime compartments, and fill it weekly (not daily)
6. For a meal plan, work with our nutritionist.
7. At any time after you are on the hormonal aspect of the program, you can begin a light exercise program, then work up as tolerated;
8. Put all to do items (re-tests to be done in 1 month, 3 months, etc.) on your calendar now.
9. Use a binder to organize your materials and make sections:
√ “To Do” Recommendations
√ Lab requisitions
√ Specialty Lab test results
√ Tracking
General directions for Herbs
a. Mix Tinctures in a small amount of unsweetened organic Pomegranate Juice-can mix all doses for one day in a jar.
b. Avoid sweets, high glycemic index foods completely.
c. Can mix all herbs together; can take with food, but best on empty stomach
d. To avoid the alcohol (which is how the herbs are prepared) please prepare the next days dose (or 2-3 days of herbs) at night, add some boiling water, and let the herbs sit overnight. The alcohol will evaporate by morning.
The Complete List of Supplements, Diet, and other treatments is in a separate document.
Explanation and directions regarding oxalates
Oxalates are compounds that naturally exist in many food items. Often found in food considered healthy – such as spinach and almonds – oxalates can cause digestive issues.
Oxalates often give foods their bitter taste and are thought to be compounds meant to protect the plant from predators, such as ourselves. (They aren’t doing a very good job, are they?) The problem with oxalates is we cannot digest them. They pass through the gastrointestinal tract and can contribute to common gut issues such as constipation, gas, bloating, diarrhea, and more. Oxalates also bind to metal ions and form precipitates, which can cause problems. In the case of calcium, this combination can result in kidney stones.
“Most importantly, it’s a good idea to be aware of your oxalate intake. Foods that are highest in
oxalates include:”
1. Sesame seeds
2. Spinach
3. Rhubarb
4. Rice bran
5. Bran flakes
6. Almonds
7. Miso soup
8. Navy beans
9. Beets
10. Dark chocolate
11. Berries
12. Potato chips
13. French fries
14. Nut butters
You might be starting to get worried I’m going to tell you that you shouldn’t eat these foods, so let me cut right to the chase…
High oxalate foods are not a problem for everyone. I’m not telling you cut these out of your diet, I’m only bringing to your attention an important factor that could explain your mysterious digestive issues. Especially for those with healthy, nutrient dense diets, oxalates could be the answer to your gut problems you’ve been looking for!
Should you worry about oxalates?
If you aren’t having issues with your gut and are generally healthy, you shouldn’t worry too much about your oxalate intake. Though if you’re the health-conscious type who’s adding handfuls of spinach to your smoothie each day, you might want to consider toning it back a notch – even if you don’t have any issues yet.
In general, those who are affected by recurrent kidney stones, gut issues, autoimmune disease, and other chronic conditions should examine their oxalate intake. If you have any of the following conditions, you might want to try scaling back you oxalate intake to see if it affects your health positively.
· Kidney stones
· Leaky gut syndrome
· Irritable bowel syndrome (IBS)
· Inflammatory bowel disease (IBD)
· Small intestinal bacterial overgrowth (SIBO)
· Autoimmune diseases such as chronic fatigue syndrome
· Nutrient deficiency (could be due to malabsorption)
· Chronic inflammation related diseases
· Vulvodynia is often caused by excessive oxalates
Bottom line is too many oxalates can mess with your digestion.
How do oxalates interact with digestion?
As a rule, you don’t want your body to absorb oxalates. If oxalates pass through the GI tract without causing problems, then they aren’t much of an issue. A major concern is when oxalates are consumed alongside a gut condition, like leaky gut syndrome, which could increase the amount of oxalates absorbed by the body. Those with regular kidney stones have been found to have a higher rate of oxalate absorption. And probiotics have been shown to reduce the absorption rate of oxalates, probably through improved gut health.
Are there benefits of oxalates?
Oxalates are not completely understood, though studies suggest they could act like chelators – meaning they help prevent toxin absorption by binding to harmful substances.
Oxalates could also work like fiber. At one point in time we thought insoluble fiber wasn’t good for us because it couldn’t be absorbed. We now know there are many benefits to insoluble fiber, including bulking up stool and aiding in moving waste through digestion. The uncertainty surrounding the exact nature of oxalates means you don’t need to over worry about them, though they are important to be aware of – everyone reacts differently to oxalates and you may or may not be affected.
Healthy eaters often have high oxalate diets.
Those with high oxalate intake are usually eating a diet that is considered healthy, such a vegan, vegetarian, raw food diets, Paleo, ketogenic, and other low carb diets.
It can be incredibly confusing when those who eat really clean experience gut issues similar to those who are eating junk! A review that examined oxalate intake of 240,681 individuals in three studies found the average oxalate intake is around 200 mg per day and about 40 percent of oxalates in a diet came from spinach.
To give you a better idea of how high spinach is in oxalates – just one cup of spinach contains 225 mg of oxalates! You can see how easy it could be to consume the average amount of oxalates. Keep in mind, there is no recommended dietary allowance (RDA) for oxalates. These numbers are averages and by no means a recommendation. Also, I’m not suggesting you should completely avoid high oxalate foods, everyone differs in their ability to pass oxalates through their digestive tract. Remember, the gut issues that come from eating oxalates are caused by the body’s inability to absorb and digest these materials.
Reducing the impact of oxalates
Up until recently, most people were only aware of oxalates if they struggled with kidney stones. But we are realizing oxalates can have other unwanted impacts on the gut.
1. Avoid high oxalate foods – A pretty obvious recommendation. In my experience, the biggest culprits here are spinach, almonds, dark chocolate, beets, berries, nuts, and nut butters.
2. Cook oxalate containing food – When you cook (roast veggies for 30 minutes) or soak oxalate containing foods such as beans and spinach, you reduce the oxalate levels. This is why those on an all raw diet may have an increased chance of health issues caused by oxalates. Not effective for high oxalate foods: beets, spinach, swiss chard, sweet potato and amaranth.
3. Treat Candida and remove mold
4. Heal your gut – Don’t suffer quietly with digestion discomfort! If you experience gas or bloating after eating, constipation, diarrhea or any other issue that occurs regularly, I urge you to make an appointment with your functional medicine doctor. When your gut isn’t working properly it can cause poor nutrient absorption, which can compound over time and cause a cascade of health consequences. When your gut is impaired it can make it more sensitive to oxalates and vice versa – too many oxalates can lead to impaired gut health. It’s all about that balance!
5. Take Calcium with your meal – Calcium Citrate loves to bind with oxalates, which makes a larger molecule that passes through the digestive tract without absorption. Add more calcium rich foods to your diet, and if you can pair the two that’s even better. Try adding cheese to your spinach salad or enjoy a little Greek yogurt with your almonds and berries. You can also take a chewable or liquid Calcium Citrate 250mg per meal or liquid Cal-mag (Puritans Pride Brand) before meals.
6. Epsom Salt Baths-2 cups of Epsom Salt in the bath — 4 times per week — 20 minutes per bath
7. Consider your vitamin C* intake – For people with recurrent kidney stones, typically the advice is that you reduce or limit your vitamin C intake because it has been shown to increase the overall risk of developing kidney stones, and may actually increase oxalates
8. Hydrate: Drink ½ your weight in ounces. So, if you weigh 140lbs drink 70 ounces of water daily.
9. Remember to repeat the organic acids test (Great Plains Labs) after 3 months on the above measures.
*However, studies have demonstrated that vitamin C may increase the amount of oxalates you excrete in your urine. So, it may be beneficial for reducing oxalates in your body overall, especially if you aren’t affected by kidney stones.
Resources:
https://kidneystones.uchicago.edu/how-to-eat-a-low-oxalate-diet/
https://www.ncbi.nlm.nih.gov/pubmed/8335871
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300857/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541088/
http://jasn.asnjournals.org/content/18/7/2198.long
https://my.clevelandclinic.org/health/articles/kidney-stones-oxalate-controlled-diet
https://www.ncbi.nlm.nih.gov/pubmed/12631089