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Cleveland Clinic researchers have, for the first time, linked trimethylamine N-oxide (TMAO) — a gut metabolite formed during the digestion of egg-, red meat- or dairy-derived nutrients cholin…

Source: Gut bacteria linked to chronic disease

It’s been three months with a crossfit training coach at NC Fit when my coach asked me why I attend my 30min group training every day. I told my coach Brandon, that I wanted to increase 10 yr…

Source: Breaking a sweat with quick fit training at NC Fit crossfit

The one number that hasn’t really budged is the percentage of 64 year olds who have never been married. In 1960, it was 8% and in 2012, it was 7%. But the report’s authors Wendy Wang and Kim Parker…

Source: Financial instability , reason to not get married

The one number that hasn’t really budged is the percentage of 64 year olds who have never been married. In 1960, it was 8% and in 2012, it was 7%. But the report’s authors Wendy Wang and Kim Parker say this might be changing. Each decade, the percentage of people of marriageable age who are single has grown. “When today’s young adults reach their mid-40s to mid-50s, a record high share (roughly 25%) is likely to have never been married,” they write. “This is not to say that adults in their mid-40s to mid-50s who still haven’t married will never marry, but our analysis suggests that the chance of getting married for the first time after age 54 is relatively small,” adds Parker.

Why aren’t people getting married anymore? The three main reasons people give for their singleness are that they haven’t found the right person (30%), aren’t financially stable enough (27%) and are not ready to settle down (22%). Many more young people are eschewing tying the knot, at least for a while, for shacking up. The researchers don’t see that as the new normal yet. “Cohabitation is much less common than marriage and cohabiting relationships are much less stable than marriages,” says Parker.”It’s hard to imagine marriage being replaced any time soon.”

But the Pew researchers teased out a bunch of other reasons by asking what people wanted in a partner.

The quality most women want in a husband, somewhat unromantically, is a secure job, followed very closely by similar ideas on raising kids, which was the quality most men wanted in a spouse. The problem is, the report points out, that young men are increasingly less likely to be employed. “In 1960, 93% of men ages 25 to 34 were in the labor force; by 2012 that share had fallen to 82%.”

My answer to What are the best ways to prevent cancer?

Answer by Connie b. Dellobuono:

1. Stronger immune system thru whole foods consumption (20% raw), avoidance of sugar and medications
2. Exercise, sufficient sleep, social volunteering functions
3. Nurture (massage, yoga,nature walks, dancing,playing music)
4. Genetic editing (CRISPR)
5. Avoidance of environmental toxins from birth to old age, breastfeeding,homebirth,less use of medications, no smoking, less use of alcohol and maintaining a normal weight, processed foods,avoidance of air pollution
6. Constant monitoring of body functions (comprehensive blood work,labs) and signs (head ache, pain,chronic cough, skin discoloration) and communicating to doctors about these signs early – not waiting to lead to chronic stage.

What are the best ways to prevent cancer?

Research shows that plant-based diets are cost-effective, low-risk interventions that may lower body mass index, blood pressure, HbA1C, and cholesterol levels. They may also reduce the number of medications needed to treat chronic diseases and lower ischemic heart disease mortality rates. Physicians should consider recommending a plant-based diet to all their patients, especially those with high blood pressure, diabetes, cardiovascular disease, or obesity.

In the HBO documentary The Weight of the Nation, it was noted that if you “go with the flow” in the US, you will eventually become obese.

In 2011, Witters reported that in some areas of the country, the rate of obesity is 39% and is increasing at a rate of 5% per year.

Risks of obesity, diabetes, hypertension, and cardiovascular disease, along with their ensuing complications (eg, behavioral health and quality-of-life problems) often go hand-in-hand and are strongly linked to lifestyle, especially dietary choices.3 Of all the diets recommended over the last few decades to turn the tide of these chronic illnesses, the best but perhaps least common may be those that are plant based.

Despite the strong body of evidence favoring plant-based diets, including studies showing a willingness of the general public to embrace them,4 many physicians are not stressing the importance of plant-based diets as a first-line treatment for chronic illnesses. This could be because of a lack of awareness of these diets or a lack of patient education resources.

National dietary guidelines for active living and healthful eating are available at http://www.ChooseMyPlate.gov.5 A typical healthful plate of food is 1/2 plant foods (nonstarchy vegetables and fruits), 1/4 whole grains or unprocessed starchy food, and 1/4 lean protein.

The goal of this article is to review the evidence supporting plant-based diets and to provide a guideline for presenting them to patients. We start with a case study and conclude with a review of the literature.

Case Study

A 63-year-old man with a history of hypertension presented to his primary care physician with complaints of fatigue, nausea, and muscle cramps. The result of a random blood glucose test was 524 mg/dL, and HbA1C was 11.1%. Type 2 diabetes was diagnosed. His total cholesterol was 283 mg/dL, blood pressure was 132/66 mmHg, and body mass index (BMI) was 25 kg/m2. He was taking lisinopril, 40 mg daily; hydrochlorothiazide, 50 mg daily; amlodipine, 5 mg daily; and atorvastatin, 20 mg daily. He was prescribed metformin, 1000 mg twice daily; glipizide, 5 mg daily; and 10 units of neutral protamine Hagedom insulin at bedtime. His physician also prescribed a low-sodium, plant-based diet that excluded all animal products and refined sugars and limited bread, rice, potatoes, and tortillas to a single daily serving. He was advised to consume unlimited non-starchy vegetables, legumes, and beans, in addition to up to 2 ounces of nuts and seeds daily. He was also asked to begin exercising 15 minutes twice a day.

The patient was seen monthly in his primary care clinic. Over a 16-week period, significant improvement in biometric outcome measures was observed. He was completely weaned off of amlodipine, hydrochlorothiazide, glipizide, and neutral protamine Hagedorn insulin. Follow-up blood pressure remained below 125/60 mmHg, HbA1C improved to 6.3%, and total cholesterol improved to 138 mg/dL. Lisinopril was gradually decreased to 5 mg daily and his diabetes is controlled with metformin alone, 1000 mg twice daily.

Definitions of Plant-Based Diets

The presented case is a dramatic example of the effect a plant-based diet can have on biometric outcomes like blood pressure, diabetes, and lipid profile. The reduction in HbA1C from 11.1% to 6.3% in 3 months is much better than would be expected with monotherapy with metformin6 or daily exercise.7 The improvement in blood pressure observed over a 4-month period with few medications is also rarely encountered in clinical practice and is likely related to a low-sodium diet and the avoidance of red meat. Because the patient was not obese and did not have significant weight loss with the diet, the dramatic improvements appear to be related to the quality of his new diet.

A healthy, plant-based diet aims to maximize consumption of nutrient-dense plant foods while minimizing processed foods, oils, and animal foods (including dairy products and eggs). It encourages lots of vegetables (cooked or raw), fruits, beans, peas, lentils, soybeans, seeds, and nuts (in smaller amounts) and is generally low fat.8,9 Leading proponents in the field have varying opinions as to what comprises the optimal plant-based diet. Ornish et al recommends allowing animal products such as egg whites and skim milk in small amounts for reversal of disease.10,11

Esselstyn, who directs the cardiovascular prevention and reversal program at the Cleveland Clinic Wellness Institute, recommends completely avoiding all animal-based products as well as soybeans and nuts, particularly if severe coronary artery disease is present.

Despite these smaller differences, there is evidence that a broadly defined plant-based diet has significant health benefits. It should be noted that the term plant-based is sometimes used interchangeably with vegetarian or vegan. Vegetarian or vegan diets adopted for ethical or religious reasons may or may not be healthy. It is thus important to know the specific definitions of related diets and to ascertain the details of a patient’s diet rather than making assumptions about how healthy it is. The following is a brief summary of typical diets that restrict animal products. A key distinction is that although most of these diets are defined by what they exclude, the plant-based diet is defined by what it includes.

• Vegan (or total vegetarian): Excludes all animal products, especially meat, seafood, poultry, eggs, and dairy products. Does not require consumption of whole foods or restrict fat or refined sugar.
• Raw food, vegan: Same exclusions as veganism as well as the exclusion of all foods cooked at temperatures greater than 118°F.
• Lacto-vegetarian: Excludes eggs, meat, seafood, and poultry and includes milk products.
• Ovo-vegetarian: Excludes meat, seafood, poultry, and dairy products and includes eggs.
• Lacto-ovo vegetarian: Excludes meat, seafood, and poultry and includes eggs and dairy products.
• Mediterranean: Similar to whole-foods, plant-based diet but allows small amounts of chicken, dairy products, eggs, and red meat once or twice per month. Fish and olive oil are encouraged. Fat is not restricted.
• Whole-foods, plant-based, low-fat: Encourages plant foods in their whole form, especially vegetables, fruits, legumes, and seeds and nuts (in smaller amounts). For maximal health benefits this diet limits animal products. Total fat is generally restricted.

Benefits of Plant-Based Diets

The goal of our diet should be to improve our health. In this section, we will review the literature for key articles that demonstrate the benefits of plant-based diets. Our review consists of existing studies that include vegan, vegetarian, and Mediterranean diets.

Obesity

In 2006, after reviewing data from 87 published studies, authors Berkow and Barnard13 reported in Nutrition Reviews that a vegan or vegetarian diet is highly effective for weight loss. They also found that vegetarian populations have lower rates of heart disease, high blood pressure, diabetes, and obesity. In addition, their review suggests that weight loss in vegetarians is not dependent on exercise and occurs at a rate of approximately 1 pound per week. The authors further stated that a vegan diet caused more calories to be burned after meals, in contrast to nonvegan diets which may cause fewer calories to be burned because food is being stored as fat.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662288/

My answer to Does eating eggs impede healing? If so, why?

Answer by Connie b. Dellobuono:

Eggs are important for healing because they contain 9 essential amino acids, most athletes need it for muscle building and my dad used to drink raw eggs to heal his TB (lungs). Histidine () and Leucine are two of the 9 essential amino acids in eggs. Eggs plus Vitamin B rich foods are happy foods, helping happy hormones in the brain.
Eggs contain Histidine which is an amino acid that is used to develop and maintain healthy tissues in all parts of the body, particularly the myelin sheaths that coat nerve cells and ensure the transmission of messages from the brain to various parts of the body. It may be useful for treatment of mental disorders as well as certain types of sexual dysfunction. Histidine levels in the body must be balanced to ensure good mental and physical health. High levels of this amino acid have been linked to the presence of psychological disorders such as anxiety and schizophrenia, while low levels of histidine are thought contribute to the development of rheumatoid arthritis and the type of deafness that results from nerve damage. Taking histidine supplements may help relieve symptoms of rheumatoid arthritis.
Histidine in eggs is important to normal sexual functioning, because it gets converted into histamine, a chemical needed to stimulate sexual arousal. When taken together with vitamin B3 (niacin) and vitamin B6 (pyridoxine), histidine can increase sexual pleasure by boosting histamine levels in the body. Histamine is also needed to help the immune system know when the body is experiencing an allergic reaction, and for the production of gastric juices needed for normal digestion. Research suggests that histidine also acts as a natural detoxifier, protecting against radiation damage, and removing heavy metals from the system. It may even help prevent the onset of AIDS—histidine is crucial to the production of both red and white blood cells. Like other amino acids, histidine is found in many high-protein foods such as raw eggs.
Leucine in eggs helps regulate blood sugar
Leucine works with the amino acids isoleucine and Valine to repair muscles, regulate blood sugar, and provide the body with energy. It also increases production of growth hormones, and helps burn visceral fat, which is located in the deepest layers of the body and the least responsive to dieting and exercise.
Leucine, Isoleucine, and Valine are branched-chain amino acids (BCAAs), and all three of them help promote muscle recovery after exercise. Leucine is the most effective BCAA for preventing muscle loss because it breaks down and is converted to glucose more quickly than isoleucine and valine. Increased glucose supplies prevent the body’s cannibalization of muscle for energy during intense workouts, so it is no surprise that this amino acid supplement is popular among professional body builders. Leucine also promotes the healing of bones, skin, and muscle tissue after traumatic injury, and is often recommended for those recovering from surgery. Because it is so easily converted to glucose, leucine helps to regulate blood sugar; a deficiency of leucine produces symptoms similar to those of hypoglycemia, which may include headaches, dizziness, fatigue, depression, confusion, and irritability.
Histamine is also essential in defending the body against invasion by potentially disease-causing agents such as bacteria, viruses and other foreign invaders. Histamine is made and stored within white blood cells (leukocytes) such as mast cells in tissues and basophils that circulate in blood. When the immune system is activated in response to foreign material entering the body, histamine is the first "defence chemical", or more correctly, inflammatory mediator, released in the process called inflammation.
Foods with High Histamine levels: Long cooked or leftover meat, Most Alcohol (Wine, Beer, Cider, Fermented Drinks), Yeast, Fish that is not immediately gutted after catching, Aged Fish (Canned, Smoked), Tomatos (Fresh or Processed), Pickled, Fermented & Cultured Foods Sauerkraut Pickles, Kimchee, Soy Sauce, Tamari, Miso), Smoked & Cured Meats (Ham, Sausage, Salami), Shell Fish, Red Beans, Nuts, Chocolate, Citrus Fruit, Wheat Based Foods, Vinegar (Salad Dressings, Mustard, Ketchup, Mayonnaise), Spices & Seasonings (Cinnamon, Nutmeg, Hot Peppers, Cloves, Anise, Curry, Chili Powder, Overripe Fruits, Yogurt & Kefir (depends upon the cultures used), Canned Food ( additives & preservatives), Soy Products, Mushrooms, Dried Fruits, Cola, Raw & Undercooked Egg (Whites in particular)

Does eating eggs impede healing? If so, why?

My answer to How many hours does it take normally for the stomach to empty totally after a good meal. Is it a good …

Answer by Connie b. Dellobuono:

It takes 4 hrs to digest meat and 30 min to digest eggs. Constipation occurs often in over medication adults. Pineapple and papaya have strong digestive enzymes important for digestion. Eat whole foods, move and exercise often and chew your food well. When you do drink coffee in the early morn before exercise, it is a stimulant helping your bowel movement although it is avoided by those who wants to lose stomach fat.

How many hours does it take normally for the stomach to empty totally after a good meal. Is it a good eating habit not to eat during this…

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My answer to How can I prevent stomach acid in my sleep without needing medication?

Answer by Connie b. Dellobuono:

From Dr Mercola:
Ultimately, the answer to heartburn and acid indigestion is to restore your natural gastric balance and function. Eating large amounts of processed foods and sugars is a surefire way to exacerbate acid reflux as it will upset the bacterial balance in your stomach and intestine. Instead, you'll want to eat a lot of vegetables and other high-quality, ideally organic, unprocessed foods. Also, eliminate food triggers from your diet. Common culprits here include caffeine, alcohol, and nicotine products.
Next, you need to make sure you're getting enough beneficial bacteria from your diet. This will help balance your bowel flora, which can help eliminate H. pylori bacteria naturally without resorting to antibiotics. It will also aid in proper digestion and assimilation of your food. Ideally, you'll want to get your probiotics from fermented foods. If you aren't eating fermented foods, you most likely need to supplement with a probiotic on a regular basis. Ideally, you'll want to include a variety of cultured foods and beverages in your diet, as each food will inoculate your gut with a variety of different microorganisms. Fermented foods you can easily make at home include:
•Fermented vegetables
•Chutneys
•Cultured dairy, such as yoghurt, kefir, and sour cream
•Fish, such as mackerel and Swedish gravlax
Are You Suffering a Drug Side Effect?
Besides these underlying conditions, please beware that certain prescription and over-the-counter (OTC) medications can also cause heartburn. Common culprits include anxiety medications and antidepressants, antibiotics, blood pressure medications, nitroglycerin, osteoporosis drugs, and pain relievers.
If your heartburn is caused by a medication you're taking, the answer is, of course, to address what, when, and how you're taking that drug. Please do not make the mistake of simply adding yet another drug to counteract this side effect. WebMD4 offers a number of helpful tips for how to address drug-induced heartburn, such as:
• Avoid taking more than the recommended or prescribed dose
• Some medications are best taken on an empty stomach, while others are less likely to cause side effects like heartburn when taken with a meal. Check the label for instructions, or ask your doctor or pharmacist for advise on when and how to take your medication
• Ask your doctor or pharmacist to review ALL the medications and supplements you're taking to see if one or more of them cause heartburn.
Changing the dose or switching to another medication may be advisable to ease your heartburn. Some drugs may be available in cream form rather than a pill, which would be far less likely to cause heartburn
• Avoid laying down right after taking your medication
• Drink some ginger tea

How can I prevent stomach acid in my sleep without needing medication?

Hospitals significantly increased their adoption of key patient engagement functionalities between 2012 and 2015. There was a seven-fold increase in the percent of hospitals that provided patients …

Source: Electronic Capabilities for Patient Engagement among U.S. Non-Federal Acute Care Hospitals: 2012-2015

Hospitals significantly increased their adoption of key patient engagement functionalities between 2012 and 2015. There was a seven-fold increase in the percent of hospitals that provided patients with the capability to electronically view, download, and transmit their health information from 2013 to 2015.

Small hospitals need to adopt more health IT infrastructure.

Email motherhealth@gmail.com to help your clinic or hospital with mobile health application.

The tremendous growth in hospitals’ adoption of view, download, and transmit capabilities in a relatively short period of time points to the potential impact of the Medicare and Medicaid EHR Incentive Programs, and specifically to the measures related to view, download, and transmit that were required for Stage 2 of the program. In 2015, almost all hospitals (95%) offered patients the ability to electronically view their health information. Almost 9 in 10 hospitals enabled patients to download their health information. A lower percentage of hospitals–about 7 in 10–offered patients the ability to electronically transmit their health information.

However, this capability also grew significantly between 2014 and 2015. The potential impact of the Medicare and Medicaid EHR Incentive Programs is also demonstrated through significant increases in hospitals’ adoption of other program requirements; such as the ability of patients to electronically send or receive secure messages from their health care provider.

There is evidence of both growth and variation in hospital adoption of view, download, and transmit capabilities. In 2013, no states had 40% or more of their hospitals with these three electronic capabilities; whereas by 2015, all states had 40% or more of their hospitals with these three capabilities. Hospitals’ adoption of view, download, and transmit capabilities varies by type of hospital. Large hospitals provide view, download, and transmit capabilities to patients at higher rates compared to CAHs and medium to small size hospitals. Almost 8 in 10 large hospitals have all 3 capabilities while only about 6 in 10 CAHs have all 3 capabilities.

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http://dashboard.healthit.gov/evaluations/data-briefs/hospitals-patient-engagement-electronic-capabilities-2015.php#figure2

Women should sleep early as they wake up early, a natural body rhythm for women based on the study done by a team from McGill University had 15 men and 11 women come and spend 36 hours in the lab. …

Source: A woman’s body clock is shifted to a more easterly time zone

Women should sleep early as they wake up early, a natural body rhythm for women based on the study done by a team from McGill University had 15 men and 11 women come and spend 36 hours in the lab. They subjected the participants to a “cat nap” paradigm, where they’d raise and lower the lights, so that the participants slept for an hour and rose for an hour. They measured levels of melatonin, the central sleep hormone and other, subjective variables, like wakefulness and sleepiness.

The pineal gland produces melatonin, a serotonin derived hormone which modulates sleep patterns in both circadian and seasonal cycles. It helps maintain circadian rhythm and regulate reproductive hormones. Menopausal women have less melatonin and as we age we produce less of this hormone.

About Melatonin

Circadian rhythm

In animals, the primary function is regulation of day-night cycles. Human infants’ melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am.^[48] Human melatonin production decreases as a person ages.^[49] Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.^[50]

Antioxidant

Besides its function as synchronizer of the biological clock, melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant as discovered in 1993.^[51] In many less-complex life forms, this is its only known function.^[26] Melatonin is an antioxidant that can easily cross cell membranes^[52] and the blood–brain barrier.^[5][53]This antioxidant is a direct scavenger of radical oxygen and nitrogen species including OH^•, O^•₂⁻, and NO^•.^[54][55] Melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.^[55] Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.^[56]An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also scavengers in what is referred to as the cascade reaction.^[26] Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic properties. When compared to synthetic, mitochondrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a comparable protector against mitochondrial oxidative stress.^[57]

Immune system

While it is known that melatonin interacts with the immune system,^[58][59] the details of those interactions are unclear. Antiinflammatory effect seems to be the most relevant and most documented in the literature.^[60] There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production,^[61] and by doing this, counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease^[62] including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.

In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.

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Possible effect of melatonin on sleep-related postural mechanisms

Experimental and clinical evidences indicate that endocrine mechanisms, particularly involving the pineal gland, exert a role in the development of postural deficits leading to the occurrence of idiopatic scoliosis (IS). In particular, experiments performed in bipedal animals have shown that removal of the pineal gland, which secretes melatonin (M), induced a scoliosis, and that in such preparations, administration of this hormone prevented the development of this deformity (cf. 131). It appears also that adolescents with IS showed a reduced level of serum M with respect to age-related control subjects. The possible mechanisms involved in the M regulation of the tonic contraction of the axial musculature have been discussed.

It is known that the pineal gland is implicated in the control of circadian rhythms, including the sleep-waking cycle, and that during this cycle there are prominent changes in postural activity, which affect not only the limbs, but also the axial musculature. These changes are characterized by a decrease followed by a suppression of postural activity, which occur particularly during transition from wakefulness to synchronized sleep and, more prominently, to rapid eye movement (REM) sleep.

Episodes of postural atonia may also occur during the cataplectic episodes, which are typical of narcolepsy. Cholinergic and/or cholinoceptive neurons located in the dorsal pontine reticular formation (pRF) and the related medullary inhibitory reticulospinal (RS) system, intervene in the suppression of posture during REM sleep, as well as during the cataplectic episodes which occur in narcolepsy.

These structures are under the modulatory (inhibitory) influence of the dorsomedial and the dorsolateral pontine tegmentum, where serotoninergic raphe nuclei (RN) neurons and noradrenergic locus coeruleus (LC) neurons are located. We postulated that M may act not only on the circadian pacemaker, but also directly on the pontine tegmental structures involved in the regulation of posture during the animal states indicated above.

This hypothesis is supported by the facts that:

• 1) the dorsal pRF may contain specific binding sites for M;
• 2) this structure is particularly sensitive to M in adolescents, as well as in adult subjects affected by narcoleptic disturbances leading to cataplexy;
• 3) M increases the release of serotonin (5-HT), a neurotransmitter which enhances the postural tone by acting on the dorsal pRF: on the other hand, deficits in M levels may lower the activity of the serotoninergic raphe system, thus leading to a decrease or suppression of postural activity similar to that occurring either during REM sleep or during the cataplectic episodes typical of narcoleptic patients;
• 4) IS patients may show episodes of sleep apnea, a phenomenon which has been attibuted to a reduced tonic contraction of primary and accessory respiratory muscles during REM, resulting from a reduced release of 5-HT at dorsal pontine level.

It has been postulated that, if the reduced M and 5-HT levels are subliminal to produce a complete suppression of posture under the conditions reported above, the reduced postural tone, which results from this condition may lead to the development of IS, due to hypotonia which affects the axial musculature.

M secretion could be regulated not only by the activity of the serotoninergic raphe neurons projecting to the pineal gland, but probably also by the activity of noradrenergic LC neurons.

It is likely that the development of IS, which results from a reduced level of M and 5-HT, may occur provided that the noradrenergic LC inhibition of the pontine structures is impaired. Such impairment could depend upon genetic factors, similar to those postulated to play a role in narcolepsy.

In conclusion, the possibility exists that an impaired activity of brain monoaminergic systems may lead to disfunction in the production of M, which is apparently an important factor in the etiopathogenesis of IS.

http://www.ncbi.nlm.nih.gov/pubmed/12004644