Assessment of the Thyroid: Achilles Tendon Reflex (Woltman’s Sign)

Quotes by Ray Peat, PhD:
“One of the oldest tests for hypothyroidism was the Achilles tendon reflex test in which the rate of relaxation of the calf muscle corresponds to thyroid function–the relaxation is slow in hypothyroid people. Water, sodium, and calcium are more slowly expelled by the hypothyroid muscle. Exactly the same slow relaxation occurs in the hypothyroid heart muscle, contributing to heart failure, because the semi-contracted heart can’t receive as much blood as the normally relaxed heart. The hypothyroid blood vessels are unable to relax properly, contributing to hypertension. Hypothyroid nerves don’t easily return to their energized relaxed state, leading to insomnia, parasthesias, movement disorders, and nerves that are swollen and very susceptible to pressure damage.”

“The thyroid hormone keeps the cellular energy high, the adrenaline low, and reflexes strong. It undoubtedly has an important effect on both perception and responses. In the high energy, expansive state, with tresholds raised, strong stimulus could evoke a strong response. Things are bigger, possibilities are greater.”

“Checking the relaxation rate of the Achilles reflex is a quick way to check the effect of the thyroid on your nerves and muscles; the relaxation should be instantaneous, loose and floppy.”

“There are several convenient indicators of the metabolic rate–the daily temperature cycle and pulse rate (the temperature should rise after breakfast), the amount of water lost by evaporation, and the speed of relaxation of muscles (Achilles reflex relaxation).”

“Measuring the speed and relaxation of the Achilles tendon reflex twitch is a traditional method for judging thyroid function, because in hypothyroidism the relaxation is visibly delayed.”

Delayed relaxation of the muscle stretch reflex (Woltman’s Sign) occurs in hypothyroidism. The achilles tendon reflex is a scientific way to assess thyroid function. The foot should plantar flex quickly and then return immediately to its starting position or beyond with no hesitation if the metabolism is healthy. No response or a very slow return back to original position are indicative of low metabolism.

J Clin Neurosci. 2013 Mar 18. pii: S0967-5868(13)00040-4. doi: 10.1016/j.jocn.2012.09.047. [Epub ahead of print]
The origin of Woltman’s sign of myxoedema.
Burkholder DB, Klaas JP, Kumar N, Boes CJ.
Woltman’s sign of myxoedema, named after Henry Woltman in 1956, is the delayed relaxation phase of the muscle stretch reflex in patients with myxoedema. Although a change in these reflexes was mentioned as being clinically evident possibly as early as the 1870s, no formal description was published until 1924 when William Calvert Chaney objectively quantified the change. Woltman was involved in training Chaney, and it has been proposed that he guided Chaney’s study of these reflexes. Despite the attachment of Woltman’s name to the eponym, little evidence exists that directly links him to the first objective study of the muscle stretch reflex in myxoedema performed by Chaney.

Woltman’s Sign of Hypothyroidism
Mark A. Marinella

Minerva Med. 1976 Oct 27;67(51):3325-34.
[Achilles reflexogram and hemodynamic parameters in the evaluation of thyroid function].
[Article in Italian]
Franco G, Malamani T.
Among the numerous techniques designed to explore thyroid function, two which examine important peripheral aspects are considered: Achilles osteotendinous reflectivity (determination of contraction time and relaxation time of the gastrocnemius muscle) and the response of the cardiovascular system to thyroid hormones (determination of the time of onset of Korotkoff’s sound and that of the brachial sphygmic wave). Comparison of the results obtained with these two techniques in a group of 60 euthyroid subjects, 17 hypothyroid and 25 hyperthyroid cases, shows that the techniques are comparable as regards precision, reproducibility, and sensitivity and are of indubitable importance for the assessment of thyroid function through the study of two of its peripheral aspects.

Probl Endokrinol (Mosk). 1982 Jan-Feb;28(1):34-8.
[Reflexometry as a supplementary study method in thyroid hypofunction].
[Article in Russian]
Gaĭdina GA, Matveeva LS, Lazareva SP.
A correlation was established between the time of the Achilles reflex and the biochemical characteristics of thyroid function (total thyroxin and triiodothyronine levels, thyroxin-binding capacity of the blood serum proteins, the basal TTH level) in patients with grave and moderately expressed hypothyroidism. This correlation was retained during the substitution therapy: however, the reflex time recovery was retarded as compared to the degree of manifestation of the clinical symptoms and normalization of the biochemical parameters. The time of the Achilles jerk may serve as an additional criterion in evaluating the hypothyrosis severity and the effect of the treatment.

J Assoc Physicians India. 1990 Mar;38(3):201-3.
Ankle reflex photomotogram in thyroid dysfunctions.
Khurana AK, Sinha RS, Ghorai BK, Bihari N.
The tap to half relaxation time of tendon achilles reflex was measured in thirty control subjects, forty-five thyrotoxic and sixty hypothyroid patients. The half relaxation time in the control males and females was 279.33 +/- 76.39 msec and 320.00 +/- 52.37 msec. respectively. In thyrotoxic males and females the half relaxation time was 256.67 +/- 31.62 msec (P less than 0.01) and 252.50 +/- 47.68 msec (P less than 0.01) respectively. Amongst the hypothyroid male and female patients the half relaxation time was 405.0 +/- 35.56 msec (P less than 0.01) and 422.5 +/- 115.36 (P less than 0.01) respectively. As all these values were statistically significant, we consider the photomotographic measurement of ankle reflex as an important aid to the diagnosis of thyroid hormone imbalances.

Aust Fam Physician. 1976 May;5(4):550-9, 561.
A screening test for thyroid function.
Goodman E.
The Achilles tendon reflex half relaxation time measurement (ART) has been used by many physicians both as a diagnostic test and for the assessment of progress in thyroid gland malfunction. Reference is made to some results obtained in Melbourne and in other countries using different methods of measurement of the ART for these purposes. In a series of 2064 patients referred to the Shepherd Foundation Centre, the Achilles tendon reflex half relaxation time was measured by means of the SMI Reflexometer and a comparison was made in each case with a laboratory estimation of the T3 resin uptake and T4 total thyroxine iodine and the Free Thyroxine Index (FTI). Reference is made to a survey conducted among referring doctors where opinions were sought as to the clinical usefulness of different tests including the Achilles tendon reflex time measurement.

Probl Endokrinol (Mosk). 1987 May-Jun;33(3):6-9.
[Changes in the duration of the Achilles reflex in euthyroid goiter in children].
[Article in Russian]
Gaĭdina GA, Alekseeva RM, Bobrovskaia TA, Lazareva SP.
Changes in the duration of the Achilles reflex were studied in subclinical disturbances of thyroid function. For this purpose the duration of the Achilles reflex, the levels of T4, T3, iodine protein bound TSH and cholesterol were investigated in children admitted to hospital with the general diagnosis of the “euthyroid goiter”. Clinical and laboratory findings revealed subclinical types of the diffuse toxic goiter, hypothyrosis, chronic thyroiditis, endemic goiter, nodular goiter, pubertal struma and sporadic euthyroid goiter. The aim of the study was to define the diagnostic importance of reflexometry in subclinical disorders of thyroid function and to assess the relationships between metabolic derangements and the duration of the Achilles reflex. Changes in the duration were shown to correspond to disorder of thyroid function. In 76% of the cases reflexometry brought about the correct assessment of the patient’s thyroid status. A significant conformity of the levels of TSH, T3, T4 to the duration of the Achilles reflex was shown.

Med Klin. 1970 Nov 6;65(45):1973-82.
[Validity of Achilles tendon reflex measurement during thyroid gland function disorders].
[Article in German]
Gillich KH, Krüskemper HL, Stendel A.

“A study published in the Journal of Clinical Endocrinology and Metabolism assessed the level of hypothyroidism in 332 female patients based on a clinical score of 14 common signs and symptoms of hypothyroidism and assessments of peripheral thyroid action (tissue thyroid effect). The study found that the clinical score and ankle reflex time correlated well with tissue thyroid effect but the TSH had no correlation with the tissue effect of thyroid hormones (118). The ankle reflex itself had a specificity of 93% (93% of those with slow relaxation phase of the reflexes had tissue hypothyroidism) and a sensitivity of 77% (77% of those with tissue hypothyroidism had a slow relaxation phase of the reflexes) making both the measurement of the reflex speed and clinical assessment a more accurate measurement of tissue thyroid effect than the TSH.” -from How Accurate is TSH Testing?

J Clin Endocrinol Metab. 1997 Mar;82(3):771-6.
Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls.
Zulewski H, Müller B, Exer P, Miserez AR, Staub JJ.
The classical signs and symptoms of hypothyroidism were reevaluated in the light of the modern laboratory tests for thyroid function. We analyzed 332 female subjects: 50 overt hypothyroid patients, 93 with subclinical hypothyroidism (SCH), 67 hypothyroid patients treated with T4, and 189 euthyroid subjects. The clinical score was defined as the sum of the 2 best discriminating signs and symptoms. Beside TSH and thyroid hormones, we measured parameters known to reflect tissue manifestations of hypothyroidism, such as ankle reflex relaxation time and total cholesterol. Classical signs of hypothyroidism were present only in patients with severe overt hypothyroidism with low T3, but were rare or absent in patients with normal T3 but low free T4 or in patients with SCH (normal thyroid hormones but elevated basal TSH; mean scores, 7.8 +/- 2.7 vs. 4.4 +/- 2.2 vs. 3.4 +/- 2.0; P < 0.001). Assessment of euthyroid subjects and T4-treated patients revealed very similar results (mean score, 1.6 +/- 1.6 vs. 2.1 +/- 1.5). In overt hypothyroid patients, the new score showed an excellent correlation with ankle reflex relaxation time and total cholesterol (r = 0.76 and r = 0.60; P < 0.0001), but no correlation with TSH (r = 0.01). The correlation with free T4 was r = -0.52 (P < 0.0004), and that with T3 was r = -0.56 (P < 0.0001). In SCH, the best correlation was found between the new score and free T4 (r = -0.41; P < 0.0001) and TSH (r = 0.35; P < 0.0005). Evaluation of symptoms and signs of hypothyroidism with the new score in addition to thyroid function testing is very useful for the individual assessment of thyroid failure and the monitoring of treatment.

Woltman’s Sign in the bicep tendon:
CMAJ August 12, 2008 vol. 179 no. 4 387
A classic sign of hypothyroidism: a video demonstration
Sanju Cyriac MD, Sydney C. d’Souza MD, Dhiraj Lunawat MBBS, Pai Shivananda MD, Mukundan Swaminathan MBBS

Video showing the Woltman sign in the bicep tendon of a 55-year-old woman

A 55-year-old woman presented to hospital with a 2-month history of facial puffiness, constipation, hoarse voice, fatigue and cold intolerance. She had no history of illness, and she was not taking any medication. On examination, her vital signs were normal, and she was not in distress. Her voice was hoarse, and she had facial and pedal edema, yellow skin and delayed relaxation of deep tendon reflexes in her upper and lower limbs (Figure 1, Video 1, available online at www.cmaj.ca/cgi/content/full/179/4/387/DC1). The results of laboratory investigations revealed severe hypothyroidism, which was successfully managed with thyroid hormone replacement therapy.

Severe hypothyroidism is rarely seen in clinical practice in the developed world because of the widespread availability of thyroid-stimulating hormone and assays to detect thyroid hormone. Symptoms of hypothyroidism include fatigue, cold intolerance, dyspnea, weight gain, constipation, hair loss, dry skin and menstrual irregularities. Typical findings on physical examination include dry coarse skin, periorbital and pedal edema, bradycardia, thin hair and pleural effusions.

Delayed relaxation of deep tendon reflexes (Woltman sign)1 is seen in about 75% of patients with hypothyroidism and has a positive predictive value of 92% in overtly hypothyroid patients.2 In unaffected patients, the relaxation time for deep tendon reflexes is 240–320 ms. Delays in relaxation time in patients with hypothyroidism appears to be proportional to the level of thyroid-hormone deficiency. As sensitive blood assays become more widely available around the world, the Woltman sign is likely to become obsolete as a diagnostic tool.

Posted in General.

Tagged with achilles tendon reflex, basal, biceps tendon reflex, hung up, hypothyroidism, metabolism, myxoedema, Ray Peat, reflexes, thyroid, TSH, Woltman's Sign.

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By Team FPS – December 5, 2011

“Normal” TSH: Marker for Increased Risk of Fatal Coronary Heart Disease

Also see:
W.D. Denckla, A.V. Everitt, Hypophysectomy, & Aging
Inflammatory TSH
Thyroid Status and Cardiovascular Disease
The Cholesterol and Thyroid Connection
High Blood Pressure and Hypothyroidism
A Cure for Heart Disease
Hypothyroidism and A Shift in Death Patterns

Arch Intern Med. 2008 Apr 28;168(8):855-60.
Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study.
Asvold BO, Bjøro T, Nilsen TI, Gunnell D, Vatten LJ.
BACKGROUND:
Recent studies suggest that relatively low thyroid function within the clinical reference range is positively associated with risk factors for coronary heart disease (CHD), but the association with CHD mortality is not resolved.
METHODS:
In a Norwegian population-based cohort study, we prospectively studied the association between thyrotropin levels and fatal CHD in 17,311 women and 8002 men without known thyroid or cardiovascular disease or diabetes mellitus at baseline.
RESULTS:
During median follow-up of 8.3 years, 228 women and 182 men died of CHD. Of these, 192 women and 164 men had thyrotropin levels within the clinical reference range of 0.50 to 3.5 mIU/L. Overall, thyrotropin levels within the reference range were positively associated with CHD mortality (P for trend = .01); the trend was statistically significant in women (P for trend = .005) but not in men. Compared with women in the lower part of the reference range (thyrotropin level, 0.50-1.4 mIU/L), the hazard ratios for coronary death were 1.41 (95% confidence interval [CI], 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher (thyrotropin level, 2.5-3.5 mIU/L) categories, respectively.
CONCLUSIONS:
Thyrotropin levels within the reference range were positively and linearly associated with CHD mortality in women. The results indicate that relatively low but clinically normal thyroid function may increase the risk of fatal CHD.

[TSH>1.4 equates to increased risk for coronary heart disease mortality in women. -FPS]

Posted in General.

Tagged with heart disease, hypothyroidism, T3, T4, thyroid, TSH.

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By Team FPS – December 2, 2011

Ray Peat, PhD and Concentric Exercise

Also see:
Exercise Induced Stress
Exercise and Effect on Thyroid Hormone
Exercise Induced Menstrual Disorders
Ray Peat, PhD: Quotes Relating to Exercise
Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise
Aspirin and Exercise
Synergistic Effect of Creatine and Baking Soda on Performance
Protective Carbon Dioxide, Exercise, and Performance
Does eccentric training lead to more hypertrophy than concentric training?

“Exercise physiologists, without mentioning functional systems, have recently discovered some principles that extend the discoveries of Meerson and Anokhin. They found that “concentric” contraction, that is, causing the muscle to contract against resistance, improves the muscle’s function, without injuring it. (Walking up a mountain causes concentric contractions to dominate in the leg muscles. Walking down the mountain injures the muscles, by stretching them, forcing them to elongate while bearing a load; they call that eccentric contraction.) Old people, who had extensively damaged mitochondrial DNA, were given a program of concentric exercise, and as their muscles adapted to the new activity, their mitochondrial DNA was found to have become normal.”

“The brain’s role in protecting against injury by stress, when it sees a course of action, has a parallel in the differences between concentric (positive, muscle shortening) and eccentric (negative, lengthening under tension) exercise, and also with the differences between innervated and denervated muscles. In eccentric exercise and denervation, less oxygen is used and less carbon dioxide is produced, while lactic acid increases, displacing carbon dioxide, and more fat is oxidized. Prolonged stress similarly decreases carbon dioxide and increases lactate, while increasing the use of fat.”

“Nerves and muscle cells should be considered together, because they respond to many things in similar ways. The membrane people don’t like to think that nerves have an contractile properties, but in fact they do twitch slightly when stimulated, showing that in the entire cytoplasm that responds to information, not the hypothetical plasma membrane. When they are overstimulated, they swell, as muscles do when they are fatigued. When a muscle is stretched while it’s trying to contract (as in running downhill; this is called “eccentric contraction”) it becomes inflamed, and the structural damage is cumulative. By exercising muscle with “concentric contractions,” allowing them to shorten against resistance, the cellular damage can be repaired.”

“Concentric resistance training has an anabolic effect on the whole body. Sprinting is probably o.k. Endurance exercise is the worst. I don’t think martial arts are necessarily too stressful.”

“Exercise, like aging, obesity, and diabetes, increases the levels of circulating free fatty acids and lactate. But ordinary activity of an integral sort, activates the systems in an organized way, increasing carbon dioxide and circulation and efficiency. Different types of exercise have been identified as destructive or repairative to the mitochondria; “concentric” muscular work is said to be restorative to the mitochondria. As I understand it, this means contraction with a load, and relaxation without a load. The heart’s contraction follows this principle, and this could explain the observation that heart mitochondria don’t change in the course of ordinary aging.”

“Cytochrome oxidase in the brain can also be increased by mental stimulation, learning, and moderate exercise, but excessive exercise or the wrong kind of exercise (“eccentric”) can lower it (Aguiar, et al., 2007, 2008), probably by increasing the stress hormones and free fatty acids. Sedentary living a high altitude has beneficial effects on mitochondria similar to moderate exercise at sea level (He, at al., 2012.”

Mech Ageing Dev. 1987 Aug;39(3):281-8.
Lack of age-dependent changes in rat heart mitochondria.
Manzelmann MS, Harmon HJ.
The effects of aging on the composition and function of cardiac mitochondria from rats exhibiting significant decreases in synaptic brain mitochondria composition and function have been studied. Cytochrome content and cytochrome absorbance wavelength maxima do not change in heart mitochondria. Respiratory activities, respiratory control ratios, ADP/O ratios, and H+/O ratios do not change with increasing age. Unlike in brain synaptic tissue, , energy output of the heart does not decrease with age.

Adv Exp Med Biol. 1995;384:185-94.
Metabolic correlates of fatigue from different types of exercise in man.
Vøllestad NK.
It is well established that muscle fatigue, defined as a decline in maximal force generating capacity, is a common response to muscular activity. To what extent metabolic factors contribute to the reduced muscle function is still debated. Metabolic effects can affect muscle through different processes, either through a reduced ATP supply or by effects on EC-coupling or crossbridge dynamics. Observations from in vitro experiments are often extrapolated to interpret fatigue mechanisms from measurements performed in vivo, without recognizing that the biochemical reactions involved can be quite different depending on such factors as activation pattern, mode and duration of exercise. During repeated submaximal contractions, there is a negligible accumulation of H+ and inorganic phosphate, and hence fatigue must be ascribed to other factors. Substrate depletion might contribute to exhaustion, but cannot explain the gradual loss of maximal force. Curiously, the energetic cost of contraction increases progressively during repeated isometric but not during concentric contractions. With contractions involving high-force or high power output, fatigue is better related to H2PO4- than to pH, but still other factors seem to play a role.

Eur J Appl Physiol. 2012 Apr;112(4):1587-92. Epub 2011 Jul 14.
Similar increases in muscle size and strength in young men after training with maximal shortening or lengthening contractions when matched for total work.
Moore DR, Young M, Phillips SM.
Training exclusively with eccentric (lengthening) contractions can result in greater muscular adaptations than training with concentric (shortening) contractions. We aimed to determine whether training-induced increases in muscle size and strength differed between muscles performing maximal lengthening (LC) or maximal shortening (SC) contractions when total external work is equivalent. Nine healthy young males completed a 9-week isokinetic (0.79 rad/s) resistance training program of the elbow flexors whereby they performed LC with one arm and an equivalent volume of total external work with the contralateral arm as SC. Training increased isometric peak torque for both LC (~10%) and SC (~20%) with no difference (P = 0.14) between conditions. There were also similar increases in isokinetic peak torque at both slow (0.79 rad/s) and fast (5.24 rad/s) shortening and lengthening peak torque for both LC (~8-10%) and SC (~9-20%). Training increased work per repetition similarly for both LC (~17%) and SC (~22%), in spite of ~40% greater work per repetition with LC. The increase in muscle cross-sectional area with training was also similar (P = 0.37) between LC (~6.5%) and SC (~4.6%). We conclude that increases in muscle size and strength with short-term unilateral resistance training are unrelated to muscle contraction type when matched for both exercise intensity (i.e. maximal contractions) and total external work.

Posted in General.

Tagged with concentric, exercise, heart, hypertrophy, mitochondria, Ray Peat, resistance training.

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By Team FPS – December 2, 2011

Green Tea and Estrogen

“Japanese women’s relative freedom from breast cancer is independent of soy products: traditional soy foods aren’t the same as those so widely used in the US, for example, soy sauce doesn’t contain the so-called soy estrogens, and tea is used much more commonly in Japan than in the US, and contains health protective ingredients. The “estrogenic” and “antioxidant” polyphenolic compounds of tea are not the protective agents (they raise the level of estrogen), but tea’s caffeine is a very powerful and general anti-cancer protectant. The influential article in Lancet (D. Ingram, Lancet 1997;350:990-994. “Phytoestrogens and their role in breast cancer,” Breast NEWS: Newsletter of the NHMRC National Breast Cancer Centre, Vol. 3, No. 2, Winter 1997) used a method known to produce false results, namely, comparing the phytoestrogens (found in large amounts in soybeans) in the urine of women with or without breast cancer. For over fifty years, it has been known that the liver excretes estrogens and other toxins from the body, and that when (because of liver inertia) estrogen isn’t excreted by the liver and kidneys, it is retained in the body. This process was observed in both animals and humans decades ago, and it is also well established that estrogen itself suppresses the detoxifying systems, causing fewer carcinogens to be excreted in the urine. Ingram’s evidence logically would suggest that the women who have cancer are failing to eliminate estrogens, including phytoestrogens, at a normal rate, and so are retaining a higher percentage of the chemicals consumed in their diets. Flavonoids and polyphenols, like our own estrogens, suppress the detoxifying systems of the body.“ -Ray Peat, PhD

J Steroid Biochem Mol Biol 1998 Feb;64(3-4):207-15,
Effects of tea polyphenols and flavonoids on liver microsomal glucuronidation of estradiol and estrone.
Zhu BT, Taneja N, Loder DP, Balentine DA, Conney AH
Administration of 0.5 or 1% lyophilized green tea (5 or 10 mg tea solids per ml, respectively) as the sole source of drinking fluid to female Long-Evans rats for 18 days stimulated liver microsomal glucuronidation of estrone, estradiol and 4-nitrophenol by 30-37%, 15-27% and 26-60%, respectively. Oral administration of 0.5% lyophilized green tea to female CD-1 mice for 18 days stimulated liver microsomal glucuronidation of estrone, estradiol and 4-nitrophenol by 33-37%, 12-22% and 172-191%, respectively. The in vitro addition of a green tea polyphenol mixture, a black tea polyphenol mixture or (-)-epigallocatechin gallate inhibited rat liver microsomal glucuronidation of estrone and estradiol in a concentration-dependent manner and their IC50 values for inhibition of estrogen metabolism were approximately 12.5, 50 and 10 microg/ml, respectively. Enzyme kinetic analysis indicates that the inhibition of estrone glucuronidation by 10 microM (-)-epigallocatechin gallate was competitive while inhibition by 50 microM (-)-epigallocatechin gallate was noncompetitive. Similarly, several flavonoids (naringenin, hesperetin, kaempferol, quercetin, rutin, flavone, alpha-naphthoflavone and beta-naphthoflavone) also inhibited rat liver microsomal glucuronidation of estrone and estradiol to varying degrees. Naringenin and hesperetin displayed the strongest inhibitory effects (IC50 value of approximately 25 microM). These two hydroxylated flavonoids had a competitive mechanism of enzyme inhibition for estrone glucuronidation at a 10 microM inhibitor concentration and a predominantly noncompetitive mechanism of inhibition at a 50 microM inhibitor concentration.

Posted in General.

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By Team FPS – December 2, 2011

PUFA, Development, and Allergy Incidence

Also see:
Nutrition and Brain Growth in Chick Embryos
Sodium Improves Premature Infant Development
PUFA Accumulation & Aging
PUFA, Fish Oil, and Alzheimers
Blood Sugar – Resistance to Allergy and Shock
Serotonin and Autism Connection
Breastfeeding benefits babies’ brains

Quotes by Ray Peat, PhD:
“Brain tissue is very rich in complex forms of fats. The experiment (around 1978) in which pregnant mice were given diets containing either coconut oil or unsaturated oil showed that brain development was superior in the young mice whose mothers ate coconut oil. Because coconut oil supports thyroid function, and thyroid governs brain development, including myelination, the result might simply reflect the difference between normal and hypothyroid individuals. However, in 1980, experimenters demonstrated that young rats fed milk containing soy oil incorporated the oil directly into their brain cells, and had structurally abnormal brain cells as a result.

Lipid peroxidation occurs during seizures, and antioxidants such as vitamin E have some anti-seizure activity. Currently, lipid peroxidation is being found to be involved in the nerve cell degeneration of Alzheimer’s disease.”

“Prenatal exposure to estrogen, to oxygen deficiency, or to unsaturated fats decreases the size of the brain at birth. There is apparently a requirement for saturated fats during development (J. M. Bourre, N. Gozlan-Devillierre, O. Morand, and N. Baumann, “Importance of exogenous saturated fatty acids during brain development and myelination in mice,” Ann. Biol. Anim., Biochim., Biophys. 19(1B), 172-180, 1979.”

“All phases of development, from gestation to aging, are altered by the presence of the unsaturated fats, and these effects correspond closely to the loss of regenerative capacity, the ability to replenish and restore tissues.”

“Experimental evidence shows that polyunsaturated (omega-3) fats retard fetal brain development, and that sugar promotes it. These facts argue against some of the currently popular ideas of the evolution of the human brain based on ancestral diets of fish or meat, which only matters as far as those anthropological theories are used to argue against fruits and other sugars in the present diet.”

Depressed Development:

Neurotoxicol Teratol. 2010 Mar-Apr;32(2):171-81. Epub 2009 Oct 7.
Excess omega-3 fatty acid consumption by mothers during pregnancy and lactation caused shorter life span and abnormal ABRs in old adult offspring.
Church MW, Jen KL, Anumba JI, Jackson DA, Adams BR, Hotra JW.
Consuming omega-3 fatty acids (omega-3 FA) during pregnancy and lactation is beneficial to fetal and infant development and might reduce the incidence and severity of preterm births by prolonging pregnancy. Consequently, supplementing maternal diets with large amounts of omega-3 FA is gaining acceptance. However, both over- and under-supplementation with omega-3 FA can harm offspring development…In conclusion, omega-3 FA over-nutrition or imbalance during pregnancy and lactation had adverse effects on life span and sensory/neurological function in old adulthood. The adverse outcomes in the Excess offspring were likely due to a “nutritional toxicity” during fetal and/or neonatal development that programmed them for life-long health disorders. The health implication is that consuming or administering large amounts of omega-3 FA during pregnancy and lactation seems inadvisable because of adverse effects on the offspring.

Another interesting association of the highly unsaturated fats and estrogen in relation to brain function is that DHA increases the entry of estrogen into the pregnant uterus, but inhibits the entry or progesterone (Benassayag, et al., 1999) which is crucual for brain cell growth. – Ray Peat, PhD

Prostaglandins Leukot Essent Fatty Acids. 1999 May-Jun;60(5-6):393-9.
Does high polyunsaturated free fatty acid level at the feto-maternal interface alter steroid hormone message during pregnancy?
Benassayag C, Rigourd V, Mignot TM, Hassid J, Leroy MJ, Robert B, Civel C, Grangé G, Dallot E, Tanguy J, Nunez EA, Ferré F.
Polyunsaturated fatty acids (PUFA) are important in pregnancy, fetal development and parturition. We measured free fatty acids (FFA), albumin and alpha-fetoprotein (AFP) in the maternal and fetal circulations of women undergoing elective Caesarean section at term. We also studied the impact of PUFAs on estrogen (ER) and progesterone receptors (PR) binding properties in vitro in the myometria of pregnant women and ex vivo in human myometrial cells in culture. FFA in intervillous blood (I) (feto-maternal interface) and maternal peripheral blood (M) were similar, while those in the umbilical vein (V) and arteries (A) were 2-4 fold lower (P<0.001). PUFA levels were low in M and 3 fold higher in I, A and V (P< 0.001); consequently C20:4 and C22:6 were most abundant in intervillous space. Albumin was uniformly distributed throughout the maternal-fetal unit, but there was a transplacental gradient in AFP. The AFP in the intervillous space had a special conformation (less immuno-reactive, more anionic), suggesting loading with PUFA. Physiological concentrations of C20:4 stimulated estradiol binding, but inhibited progestin binding. C20:4 inhibited progesterone binding by decreasing the number of binding sites, with no change in apparent affinity, in vitro in myometrial tissue and ex vivo in myometrial cells. Thus PUFA may modulate the steroid hormone message, so that the high C20:4 concentration at the maternal-fetal interface at term may help amplify the estrogen signal and inhibit the progesterone signal.

In a study of prenatal learning (habituation rate), the experimenters found that the relative absence of the supposedly essential fatty acids improved the short term and long term memory of the fetus (Dirix, et al., 2009). The size of the baby was found to be negatively associated with the highly unsaturated fatty acids DHA and AA (Dirix, et al., 2009), showing a general growth-retarding effect of these environmentally derived fats. -Ray Peat, PhD

Early Hum Dev. 2009 Aug;85(8):525-30. Epub 2009 May 27.
Associations between term birth dimensions and prenatal exposure to essential and trans fatty acids.
Dirix CE, Kester AD, Hornstra G.
BACKGROUND:
Certain essential long-chain polyunsaturated fatty acids (LCPUFAs) are considered important for fetal growth and brain development, whereas industrial trans fatty acids (mainly 18:1trans) have been associated with negative effects. The aim of this study was to investigate associations between term birth dimensions and prenatal exposure to some of these fatty acids, reflected by neonatal fatty acid concentrations at birth.
METHODS:
Data of up to 700 infant-mother pairs from the Maastricht Essential Fatty Acid Birth Cohort were used for the present study. Unadjusted and multivariable-adjusted linear regression analyses were performed to investigate associations between birth weight, birth length or head circumference and relative concentrations of docosahexaenoic acid (DHA), arachidonic acid (AA), dihomo-gamma-linolenic acid (DGLA) and trans-octadecenoic acids (18:1t) measured in phospholipids of the walls of umbilical arteries and veins, and in umbilical cord plasma and erythrocytes.
RESULTS:
After optimal adjustment, a significant negative association was observed between birth weight and umbilical plasma DHA concentrations. Negative associations were also found for AA concentrations measured in umbilical plasma and in arterial and venous vessel walls. Birth length was negatively related to arterial vessel wall AA concentrations only. A significant negative association was observed for the relationship between 18:1t in cord erythrocytes and birth weight. For DGLA no significant associations were observed.
CONCLUSIONS:
Results seem to preclude a role of DHA and AA as growth factors per se. Their negative relationships with birth dimensions may result from a limited maternal-fetal LCPUFA transfer capacity. Potential effects of 18:1t and DGLA on birth dimensions are probably small or non-existing.

When Dirix, et al., (2009) supplemented pregnant women with PUFA, they found that fetal memory was impaired. -Ray Peat, PhD

Prostaglandins Leukot Essent Fatty Acids. 2009 Apr;80(4):207-12. Epub 2009 Mar 19.
Fetal learning and memory: weak associations with the early essential polyunsaturated fatty acid status.
Dirix CE, Hornstra G, Nijhuis JG.
To study the potential associations between fetal brain functions and the early essential polyunsaturated fatty acid (ePUFA) status, fetal learning and memory were assessed by repeated habituation rate measurements (HR) in fetuses of 30, 32, 34 or 36 weeks gestational age (GA). HR tests were repeated 10 min later. Both measurements were replicated in a second session at GA 38. Fetal short-term memory (STM) and long-term memory (LTM) were calculated from these habituation rates and related to concentrations of ePUFAs and their status markers, measured in umbilical artery wall phospholipids. The only relevant associations observed were positive trends (0.010<0.050) between STM measured before 38 weeks GA and concentrations of the ePUFA status markers Mead acid and Mead acid+dihomo-Mead acid, and between LTM and levels of Osbond acid, a marker of the n-3 LCPUFA status. Although these weak associations may imply some negative relationships between fetal brain functions and the early ePUFA status, we concluded that physiological differences in the availability of these fatty acids may probably not determine the differences in these primitive brain functions during the third trimester of fetal development.

“In adults, the long-chain omega-3 fatty acids such as DHA are known to be immunosuppressive, but in tests on monocytes that are so important for proper development and regeneration (Sweeney, et al., 2001), and interfere with signals that govern their migration (Ferrante, et al., 1994).” -Ray Peat, PhD

Pediatr Surg Int. 2001 May;17(4):254-8.
Polyunsaturated fatty acids influence neonatal monocyte survival.
Sweeney B, Puri P, Reen DJ.
The n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential dietary constituents. They are potent modulators of the human immune response, and research has endeavoured to optimise the ratio of n-3 to n-6 fatty acids in the lipid emulsion component of total parenteral nutrition to harness their beneficial effects in the clinical setting. PUFAs modulate apoptosis of certain tumour cells and cell lines. Monocytes, which are major effector cells of the innate immune system, play a central role in the initiation, development, and outcome of the immune response. They are crucial in the defence against invading pathogens and are involved in the lysis of infected or malignant cells, wound healing, repair, and remodeling of tissues. In the present study we investigated whether PUFAs might evoke apoptosis in newborn monocytes. Purified cord-blood monocytes collected from uncomplicated full-term pregnancies were incubated for 24 h in complete medium in the presence or absence of one of the n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic (EPA) or the n-6 PUFA arachidonic acid (AA). Following incubation, cells were triple-labelled with annexin V, CD14, and propidium iodide prior to flow-cytometric analysis to determine the degree of cell death. All experiments were performed in triplicate and data expressed as mean +/- 1 S.D. (%). In the absence of fatty acids, 30 +/- 4% of control cord monocytes underwent apoptosis or necrosis after 24 h incubation. At a concentration of 50 microM, none of the PUFAs had a significant effect on monocyte cell death, but at a dose of 100 microM, DHA resulted in 60 +/- 4% cell death (P < 0.05) while the other PUFAs had no significant effect. In contrast, at higher concentrations (200 microM), all the PUFAs significantly increased monocyte cell death (AA: 70 +/- 5%, DHA: 86 +/- 2%, EPA: 70 +/- 4%). PUFAs thus exert a potent influence on cord monocyte cell survival in vitro. Their effect is dose-dependent and DHA appears to be the most potent of the fatty acids tested. The influence of PUFAs on neonatal monocyte-cell survival suggests a novel mechanism whereby PUFAs may modulate the immune response.

J Clin Invest. 1994 March; 93(3): 1063–1070.
Neutrophil migration inhibitory properties of polyunsaturated fatty acids. The role of fatty acid structure, metabolism, and possible second messenger systems.
A Ferrante, D Goh, D P Harvey, B S Robinson, C S Hii, E J Bates, S J Hardy, D W Johnson, and A Poulos
The n-3 polyunsaturated fatty acids (PUFA) appear to have antiinflammatory properties that can be partly explained by their biological activity on leukocytes. Since leukocyte emigration is an essential component of the inflammatory response, we have examined the effects of the n-3 PUFA (eicosapentaenoic and docosahexaenoic acids) on neutrophil random and chemotactic movement. Preexposure of neutrophils for 15-30 min to 1-10 micrograms/ml PUFA reduced the random and chemotactic migration to both FMLP- and fungi-activated complement. The inhibitory effect diminished with increasing saturation and carbon chain length, and methylation abolished this activity. Arachidonic and docosahexaenoic acids were the most active fatty acids. The PUFA concentration required to inhibit migration was dependent on cell number, suggesting that the fatty acid effects on leukocyte migration in vivo may be governed by the stage of the inflammatory response. It was concluded that the PUFA rather than their metabolites were responsible for the inhibition since: (a) antioxidants did not prevent the PUFA-induced migration inhibition and the hydroxylated intermediates were less active, and (b) inhibitors of the cyclooxygenase and lipoxygenase pathways were without effect. Inhibitors of protein kinases and calmodulin-dependent enzyme system did not prevent the PUFA-induced migration inhibition, which was also independent of phospholipase D-catalyzed hydrolysis of phospholipids. It is also shown that PUFA decrease the FMLP-induced Ca2+ mobilization.

If the very small amounts of polyunsaturated fats reaching the fetus can retard growth and brain development (Liu and Borgman, 1977; Borgman, et al., 1975) and function, it is apparently acting on some very important biological processes. The toxic effects of PUFA seen in the animal studies probably have their equivalent in humans, for example the association of childhood hyperactivity with a smaller brain. -Ray Peat, PhD

Estrogen, and another common respiratory toxin, excessive unsaturated fats, have both been demonstrated to cause the birth of small-brained, retarded animals.”-Ray Peat, PhD

Am J Vet Res. 1977 Oct;38(10):1657-9.
Influence in rats of dietary fats during the perinatal period: effects upon development and behavior of dams and offspring.
Liu YL, Borgman RF.
Female rats were fed purified rations containing 20% fat during gestation and lactation. The fat content was butter oil, an equal mixture of butter oil and lard, or safflower oil. Each litter size was reduced (at random) to 2 male and 2 female pups 1 day postpartum, and these offspring were feed a commercial ration after weaning and until they were 20 weeks of age. When dams were fed safflower oil, fewer of them produced litters after mating, and their behavior during lactation was less than optimal. Litter size and birth weights were similar in all dams producing litters. The type of fat fed to the dam in the perinatal period did not influence the growth, development, and spontaneous activity of the offspring. However, the offspring from the dams fed safflower oil exhibited poorer learning performance in a T-maze and sometimes had a longer time of inactivity following auditory stimulation than did the offspring from dams fed the other types of fats.

Am J Vet Res. 1975 Jun;36(6):795-8.
Influence of dietary fat upon rats during gestation and lactation.
Borgman RF, Bursey RG, Caffrey BC.
A comparison was made between rats fed purified rations containing different fats during gestation and lactation and rats fed a commercial ration during similar periods. The purified ration containign 20% cocoa butter did not result in appreciable differences in the mothers (body weight, behavior, litter production, and brain chemistry) or in the 1-day-old neonates (brain chemistry). The purified ration containing 20% safflower oil resulted in fewer completed gestation, in poorer maternal behavior during lactation, and in neonates with small brains. A fat-free purified ration resulted in low brain concentrations of RNA and low RNA-DNA ratios in the mothers.

Behav Brain Res. 2013 Feb 1;238:193-9. doi: 10.1016/j.bbr.2012.10.028. Epub 2012 Oct 22.
Maternal diet rich in omega-6 polyunsaturated fatty acids during gestation and lactation produces autistic-like sociability deficits in adult offspring.
Jones KL1, Will MJ, Hecht PM, Parker CL, Beversdorf DQ.
Multiple studies have reported prenatal stress as a potential risk factor for the development of autism spectrum disorder (ASD). In rodents, a significant reduction in sociability is seen in prenatally stressed offspring of genetically stress-susceptible dams. Certain dietary factors that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in adult offspring. Adults with a diet rich in omega-6 polyunsaturated fatty acids (PUFAs) display increased stress reactivity. In the current study, the effects of prenatal diet and prenatal stress on social behavior in adult offspring mice were examined. Pregnant C57BL/6J dams received either chronic variable stress or no stress, and were also placed on a control diet or a diet rich in omega-6 PUFAs, in a 2×2 design. We subsequently tested the adult offspring for sociability, anxiety, and locomotor behaviors using a 3-chambered social approach task, an elevated-plus maze, an open field task and a rotarod task. Results indicated that a maternal diet rich in omega-6 PUFAs during gestation and lactation produce changes in sociability consistent with those observed in ASD. Additionally, offspring exposed to a diet rich in omega-6 PUFAs during gestation and lactation had increased levels of anxiety in the elevated-plus maze. Prenatal stress had no effect on offspring behavior. These findings provide evidence for a possible environmental risk factor that contributes to the production of autistic-like behavior in mice.

No Improvement:

Am J Clin Nutr June 2011 vol. 93 no. 6 1293-1299
Maternal supplementation with docosahexaenoic acid during pregnancy does not affect early visual development in the infant: a randomized controlled trial
Lisa G Smithers, Robert A Gibson, and Maria Makrides
Background: The docosahexaenoic acid (DHA) intake of pregnant women is lower than estimates of the DHA accretion by the fetus, and recommendations were made to increase the DHA intake of pregnant women.
Objective: The objective of this study was to determine whether the supplementation of pregnant women with DHA improved the visual acuity of infants at 4 mo.
Design: We conducted a blinded assessment of a subset of healthy, full-term infants born to women enrolled in a double-blind, randomized controlled trial called the DHA for Maternal and Infant Outcomes (DOMInO) trial. Women were randomly assigned to consume DHA-rich fish-oil capsules (≈800 mg DHA/d in the treatment group) or vegetable oil capsules (control group) from midpregnancy to delivery. The primary outcome was the sweep visual evoked potential (VEP) acuity at 4 mo. The VEP latency at 4 mo was a secondary outcome.
Results: Mean (±SD) VEP acuity did not differ between treatment and control groups [treatment group: 8.37 ± 2.11 cycles per degree (cpd), n = 89; control group: 8.55 ± 1.86 cpd, n = 93; P = 0.55]. VEP latencies also did not differ between groups. Irrespective of the group, maternal smoking in pregnancy was independently associated with poorer VEP acuity in the infant.
Conclusions: DHA supplementation in women with singleton pregnancies does not enhance infant visual acuity in infants at 4 mo of age. Visual acuity in infancy is adversely associated with maternal smoking in pregnancy.

Am J Clin Nutr. 2011 Dec;94(6):1880S-8S. Epub 2011 Aug 17.
Effects of prenatal fish-oil and 5-methyltetrahydrofolate supplementation on cognitive development of children at 6.5 y of age.
Campoy C, Escolano-Margarit MV, Ramos R, Parrilla-Roure M, Csábi G, Beyer J, Ramirez-Tortosa MC, Molloy AM, Decsi T, Koletzko BV.
BACKGROUND:
The influence of prenatal long-chain polyunsaturated fatty acids (LC-PUFAs) and folate on neurologic development remains controversial.
OBJECTIVE:
The objective was to assess the long-term effects of n-3 (omega-3) LC-PUFA supplementation, 5-methyltetrahydrofolate (5-MTHF) supplementation, or both in pregnant women on cognitive development of offspring at 6.5 y of age.
DESIGN:
This was a follow-up study of the NUHEAL (Nutraceuticals for a Healthier Life) cohort. Healthy pregnant women in 3 European centers were randomly assigned to 4 intervention groups. From the 20th week of pregnancy until delivery, they received a daily supplement of 500 mg docosahexaenoic acid (DHA) + 150 mg eicosapentaenoic acid [fish oil (FO)], 400 μg 5-MTHF, or both or a placebo. Infants received formula containing 0.5% DHA and 0.4% arachidonic acid (AA) if they were born to mothers receiving FO supplements or were virtually free of DHA and AA until the age of 6 mo if they belonged to the groups that were not supplemented with FO. Fatty acids and folate concentrations were determined in maternal blood at weeks 20 and 30 of pregnancy, at delivery, and in cord blood. Cognitive function was assessed at 6.5 y of age with the Kaufman Assessment Battery for Children (K-ABC).
RESULTS:
We observed no significant differences in K-ABC scores between intervention groups. Higher DHA in maternal erythrocytes at delivery was associated with a Mental Processing Composite Score higher than the 50th percentile in the offspring.
CONCLUSION:
We observed no significant effect of supplementation on the cognitive function of children, but maternal DHA status may be related to later cognitive function in children. This trial was registered at clinicaltrials.gov as NCT01180933.

Allergy Incidence

Clin Exp Allergy. 2004 Feb;34(2):194-200.
Maternal breast milk long-chain n-3 fatty acids are associated with increased risk of atopy in breastfed infants.
Stoney RM, Woods RK, Hosking CS, Hill DJ, Abramson MJ, Thien FC.
BACKGROUND:
Australia has one of the highest prevalence rates internationally of allergic conditions, such as asthma and eczema. Atopy is one hallmark for the development of allergic disease and predisposes to allergic inflammation in the target organs. omega-3 (n-3) fatty acids (FAs) are thought to act as precursors to the formation of less active inflammatory mediators, with the potential to reduce inflammation.
OBJECTIVE:
To investigate whether increased n-3 FA levels in maternal breast milk are associated with a lower risk of developing atopy in infancy.
METHODS:
Subjects were part of the prospective Melbourne atopy cohort study, which involved 620 children born into families where at least one first-degree relative had an atopic disease. Some 224 women (mean age 31.4+/-4.2 (SD) years, with 73.2% (n=164) having self-reported atopy) provided either a colostrum (n=194) or 3-month expressed breast milk (EBM) sample (n=118). Maternal colostrum and 3-month EBM samples were analysed for FA content by gas chromatography. Skin prick tests (SPTs) to six common allergens were performed on infants at 6, 12 and 24 months of age and on mothers who agreed at study entry.
RESULTS:
For infants sensitized to foods at 6 months (n=29), the total n-3 FA level in the colostrum was significantly higher (P=0.004) as were levels of individual long-chain n-3 FAs, docosoapentaenoic acid (DPA, C22:5, P=0.001) and docosahexaenoic acid (DHA, C22:6, P=0.002) than in non-sensitized infants. Infants with aero-allergen sensitization at 24 months (n=30) had higher levels of the n-3 FA, DPA (P=0.002) and DHA (P=0.007), and similarly higher total n-3 FA (P=0.009) in maternal colostrum than those infants who were not sensitized.
CONCLUSION:
Higher n-3 FA levels in the colostrum do not appear to confer protection against, but may be a risk factor for, the eventual development of atopy in high-risk breastfed infants.

Clin Exp Allergy. 2008 Nov;38(11):1745-51. Epub 2008 Aug 12.
Associations between fatty acids in colostrum and breast milk and risk of allergic disease.
Lowe AJ, Thien FC, Stoney RM, Bennett CM, Hosking CS, Hill DJ, Carlin JB, Abramson MJ, Dharmage SC.
BACKGROUND:
Exposure to n-3 polyunsaturated fatty acids (PUFA) in early life is hypothesized to offer protection against atopic disease. However, there is controversy in this area, and we have previously observed that high levels of n-3 fatty acid (FA) in colostrum are associated with increased risk of allergic sensitization.
OBJECTIVE:
The aim of the study was to assess the relationship between FA profile in breast milk and risk of childhood atopic disease.
METHODS:
A high-risk birth cohort was recruited, and a total of 224 mothers provided a sample of colostrum (n=194) and/or 3-month expressed breast milk (n=118). FA concentrations were determined by gas chromatography. Presence of eczema, asthma and rhinitis were prospectively documented up to 7 years of age.
RESULTS:
High levels of n-3 22:5 FA (docosapentaenoic acid, DPA) in colostrum were associated with increased risk of infantile atopic eczema [odds ratio (OR)=1.66 per 1 standard deviation increase, 95% confidence interval (CI)=1.11-2.48], while total n-3 concentration in breast milk was associated with increased risk of non-atopic eczema (OR=1.60, 95% CI=1.03-2.50). Higher levels of total n-6 FA in colostrum were associated with increased risk of childhood rhinitis (OR=1.59, 95% CI=1.12-2.25). There was no evidence of associations between FA profile and risk of asthma.
CONCLUSION:
In this cohort of high-risk children, a number of modest associations were observed between FA concentrations in colostrum and breast milk and allergic disease outcomes. Further research in this area with larger sample sizes is needed.

Pediatr Allergy Immunol. 2006 Feb;17(1):4-10.
Atopy, eczema and breast milk fatty acids in a high-risk cohort of children followed from birth to 5 yr.
Oddy WH, Pal S, Kusel MM, Vine D, de Klerk NH, Hartmann P, Holt PG, Sly PD, Burton PR, Stanley FJ, Landau LI.
BACKGROUND:
The incidence of atopic diseases such as eczema is increasing in westernized societies. The suggestion that there is a “protective” association between the unique fatty acid composition of breast milk, particularly the omega-3 (n-3) and omega-6 (n-6) essential polyunsaturated fatty acid content, and the development of atopic disease in children was investigated in a cohort study of 263 infants born into families with a history of allergy (one or both parents had asthma, hayfever, eczema). The objectives of this study were to determine the lipid profile [specifically in relation to long-chain polyunsaturated fatty acid (LC-PUFA) composition] in maternal breast milk samples collected at 6 wk and at 6 months following birth, and to investigate the potential role of these fatty acids in modulating the phenotype of children at high genetic risk of developing atopic disease.
METHOD:
Breast milk samples were available from 91 atopic mothers at their child’s ages of 6 wk and 6 months. These samples were analysed for the fatty acid spectrum. Analysis of variance was used to detect differences between groups of outcomes (no atopy or eczema, non-atopic eczema, atopy, atopic eczema) at ages 6 months and 5 yr, and a multiple comparisons procedure was conducted to isolate the parameters producing the different results (F-test, LSD test). For the exposure variables, n-3 and n-6 fatty acids are expressed as weight percentage and as a ratio (at both time-points).
RESULTS:
The fatty acid profiles of maternal breast milk at 6 wk and 6 months were similar. An increased ratio of n-6: n-3 fatty acids in both 6 wk and 6 month milk samples was associated with non-atopic eczema (p < 0.005) but not atopy alone or atopic eczema.
CONCLUSION:
We found milk fatty acids were a significant modulator of non-atopic eczema but not atopy or atopic eczema in infants at 6 months. In mothers with a history of asthma, hayfever or eczema, their 6-month-old infants were more likely to develop non-atopic eczema if their milk had a higher ratio of n-6: n-3 LC-PUFA.

Acta Paediatr. 1996 Jun;85(6):679-83.
Phospholipid fatty acids in cord blood: family history and development of allergy.
Yu G, Kjellman NI, Björkstén B.
The fatty acid composition of umbilical cord serum phospholipids was investigated by gas chromatography in 33 infants with allergic and 35 babies of non-allergic mothers. The relative levels of the linoleic acid metabolites C20:3, arachidonic acid (AA, C20:4) and C22:4n-6, and two alpha-linolenic acid metabolites, i.e. eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, C22:6) were significantly higher in infants of allergic mothers than in non-allergic mothers (all p < 0.05). Furthermore, an altered proportional relationship between the various fatty acids in n-6 series fatty acids and between n-3 and n-6 series fatty acids was present already at birth in infants who developed allergic disease during their first 6 years of life. These observations cannot be employed for the prediction of allergy, however, as the individual variations were considerable.

“EFA Deficiency” found in Newborns:

“The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are antiinflammatory, and some of which act on the “bliss receptor,” or the cannibinoid receptor.

At birth, the baby’s mitochondria contain a phospholipid, cardiolipin, containing palmitic acid, but as the baby eats foods containing polyunsaturated fatty acids, the palmitic acid in cardiolipin is replaced by the unsaturated fats. As the cardiolipin becomes more unsaturated, it becomes less stable, and less able to support the activity of the crucial respiratory enzyme, cytochrome oxidase.” -Ray Peat, PhD

“The fatty acids of newborn humans, and other non-ruminants, reflect their mothers’ diets more closely, but Mead acid is still present in human newborns (Al, et al., 1990).” -Ray Peat, PhD

Early Hum Dev. 1990 Dec;24(3):239-48.
Biochemical EFA status of mothers and their neonates after normal pregnancy.
Al MD, Hornstra G, van der Schouw YT, Bulstra-Ramakers MT, Huisjes HJ.
The essential fatty acid (EFA) status of neonates was compared with that of their mothers by determining the fatty acid compositions of phospholipids (PL), isolated from umbilical arterial and venous tissue, blood cells (BC) and plasma, from maternal venous plasma and BC, and from non-infarcted placental tissue. The PL of umbilical arterial tissue (efferent fetal vessels) contained fewer fatty acids of the (n-6) family and more of the (n-9) family than umbilical venous tissue (afferent fetal vessel). The relative amounts of (n-6) and (n-3) fatty acids were less in arterial than in venous plasma. Mead acid, 20:3(n-9), the presence of which indicates a poor EFA status, was 5 times higher in the efferent than in afferent cord vessels. In neonatal plasma and BC it was twice as high as compared with maternal levels. In general, the fatty acid composition of the placenta PL showed a comparable pattern as neonatal venous plasma PL. These findings demonstrate that the biochemical EFA status of neonates after a normal pregnancy is not optimal. The significant correlations between neonatal and maternal EFAs indicate that the neonatal EFA status depends on the EFA content of the maternal diet.

This progressive increase [in PUFA] with age can be seen already in early childhood (Guerra, et al., 2007). -Ray Peat, PhD

Ann Nutr Metab. 2007;51(5):433-8. Epub 2007 Nov 20.
Three-year tracking of fatty acid composition of plasma phospholipids in healthy children.
Guerra A, Demmelmair H, Toschke AM, Koletzko B.
OBJECTIVES:
The fatty acid composition of plasma phospholipids reflects the dietary fatty acid intake as well as endogenous turnover. We aimed at investigating the potential tracking of plasma phospholipid fatty acid composition in children that participated in a prospective cohort study.
METHODS:
26 healthy children participated in a longitudinal study on health risks and had been enrolled after birth. All children were born at term with birth weights appropriate for gestational age. Follow-up took place at ages 24, 36 and 60 months. At each time point a 24-hour dietary recall was obtained, anthropometric parameters were measured and a blood sample for phospholipid fatty acid analysis was taken.
RESULTS:
Dietary intake of saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids at the three time points were not correlated. We found lower values for plasma MUFA and the MUFA/SFA ratio at 60 months compared to 24 months. In contrast, total PUFA, total n-6 and n-6 long-chain polyunsaturated fatty acids (LC-PUFA) were higher at 60 months. Significant averaged correlation coefficients (average of Pearson’s R for 24 versus 36 months and 36 versus 60 months) were found for n-6 LC-PUFA (r = 0.67), n-6/n-3 LC-PUFA ratio (r = 0.59) and arachidonic acid/linoleic acid ratio (r = 0.64). Partial tracking was found for the docosahexaenoic acid/alpha-linolenic acid ratio (r = 0.33). Body mass index and sum of skinfolds Z-scores were similar in the three evaluations.
CONCLUSIONS:
A significant tracking of n-6 LC-PUFA, n-6 LC-PUFA/n-3 LC-PUFA ratio, arachidonic acid/linoleic acid ratio and docosahexaenoic acid/alpha-linolenic acid ratio may reflect an influence of individual endogenous fatty acid metabolism on plasma concentrations of some, but not all, fatty acids.

Posted in General.

Tagged with allergies, allergy, asthma, autism, baby, brain, cognitive, development, DHA, eczema, EPA, fish oil, formula, gestation, infant, intelligence, lactation, liquid oils, omega 3, omega 6, PUFA, Ray Peat, saturated fat, seed oil, skin, soy, unsaturated fats.

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By Team FPS – December 1, 2011

Gerald Pollack Interviews

Also see:
ATP Regulates Cell Water
Cells, Gels and the Engines of Life
The Fourth Phase of Water: Beyond Solid, Liquid, and Vapor
Water and the Cell
Gilbert Ling

https://www.youtube.com/watch?v=BRh38KfT8pw

https://youtu.be/_HM1fgLSE2c

https://www.youtube.com/watch?v=1FZ3t3T5mGs

https://www.youtube.com/watch?v=ZuNlwbPFehQ

Posted in General.

Tagged with adsorbed water, association induction hypothesis, ATP, cardinal adsorbent, cells, charge, electric, energy, Fourth Phase of Water, function, gels, Gerald Pollack, Gilbert Ling, membrane, pumps, Ray Peat, structure, structured water, water.

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By Team FPS – November 30, 2011

Endotoxin and Obesity

Also see:
Endotoxin: Poisoning from the Inside Out
Protection from Endotoxin
Endotoxin-lipoprotein Hypothesis
Protective Bamboo Shoots
The effect of raw carrot on serum lipids and colon function
Are Happy Gut Bacteria Key to Weight Loss?

January 2009 The Journal of Lipid Research, 50, 1-2.
Endotoxin in the gut and chylomicrons: translocation or transportation?
Carl Grunfeld 2 and Kenneth R. Feingold, Associate Editor
The intestine contains trillions of microorganisms and massive amounts of endotoxin, which if absorbed from the intestinal lumen into the body would result in overwhelming septic shock and death. Recently there has been an increasing appreciation of the role of gut microorganisms and their translocation into the systemic circulation in promoting metabolic disorders including obesity and insulin resistance, as well as in the pathogenesis of very different disorders, such as inflammatory bowel disease, HIV infection, ethanol-induced liver disease, and hemorrhagic shock.

Endocr Rev. 2010 Dec;31(6):817-44. Epub 2010 Jun 30.
Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk.
Manco M, Putignani L, Bottazzo GF.
Compelling evidence supports the concepts that gut microbiota actively promotes weight gain and fat accumulation and sustains, indirectly, a condition of low-grade inflammation, thus enhancing the cardiovascular risk. Fewer Bacteroidetes and more Firmicutes seem to characterize the gut microbiota of obese people as compared with that of lean individuals. This difference translates into an increased efficiency of microbiota of obese individuals in harvesting energy from otherwise indigestible carbohydrates. Furthermore, the microbiota also seems able to favor fat accumulation. Indeed, studies performed in germ-free animals have demonstrated that conventionalization of sterile intestine with gut microbiota is associated with an enhanced expression of various lipogenic genes in different tissues, i.e., hepatic, adipose, and muscle tissues. Finally, the microbiota favors systemic exposure to the lipopolysaccharides (LPSs), large glycolipids derived from the outer membrane of Gram-negative bacteria. LPSs can cause a condition of “metabolic endotoxemia” characterized by low-grade inflammation, insulin resistance, and augmented cardiovascular risk. LPSs are a powerful trigger for the innate immune system response. Upon binding to the Toll-like receptor 4 and its coreceptors, LPSs trigger a cascade of responses ultimately resulting in the release of proinflammatory molecules that interfere with modulation of glucose and insulin metabolism, promote development and rupture of the atherosclerotic plaque, and favor progression of fatty liver disease to steatohepatitis. This review gives a comprehensive breakdown of the interaction among gut microbiota, LPSs, and the innate immune system in the development of obesity and promotion of an individual’s cardiovascular risk.

Diabetes June 2008 vol. 57 no. 6 1470-1481
Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice
Patrice D. Cani, Rodrigo Bibiloni, Claude Knauf, Aurélie Waget, Audrey M. Neyrinck, Nathalie M. Delzenne, and Rémy Burcelin
OBJECTIVE—Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases.
RESEARCH DESIGN AND METHODS—We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect.
RESULTS—We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat–fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14−/− mutant mice mimicked the metabolic and inflammatory effects of antibiotics.

Korean J Obes. 2010 Sep;19(3):78-84. Korean.
The Association between Visceral Fat and Endotoxin.
Chung JH, Kang MK, Rho JS, Yum KS.
Department of Family Medicine, Jeju National Hospital, Korea.
BACKGROUND: Visceral fat accumulation has been known to be an independent risk factor of cardiovascular disease with increased risk of diabetes. It is also associated with inflammation factor, such as adiponectin, leptin, IL-6 and IL-10. Endotoxin is also related with many inflammation factors and atherosclerosis. There are only few studies regarding the correlation between endotoxin concentration and visceral fat in adults. Thus, the purpose of this study was to investigate the relationship between visceral fat and serum endotoxin concentration in adults. METHODS: A total of 40 of subjects (26 men and 14 women) were enrolled for this study. The subjects were selected among Korean adults who visited the Department of Family Medicine from January 2009 to August 2009. Abdominal fat area was calculated from CT scan taken at the umbilical level. Serum endotoxin concentration was measured by Endo-Chek TM (Diatech Korea Co..Ltd., Seoul, Korea). RESULTS: Serum endotoxin concentration was positively correlated with visceral fat in adults (P < 0.05). CONCLUSION: Based on the results of this study, serum endotoxin concentration was positively correlated with visceral fat in adults. Further appropriate studies are required to better elucidate the relationship between visceral fat and serum endotoxin concentration among Korean adult population.

The ISME Journal advance online publication 13 December 2012
An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice
Na Fei and Liping Zhao
Lipopolysaccharide endotoxin is the only known bacterial product which, when subcutaneously infused into mice in its purified form, can induce obesity and insulin resistance via an inflammation-mediated pathway. Here we show that one endotoxin-producing bacterium isolated from a morbidly obese human’s gut induced obesity and insulin resistance in germfree mice. The endotoxin-producing Enterobacter decreased in relative abundance from 35% of the volunteer’s gut bacteria to non-detectable, during which time the volunteer lost 51.4 kg of 174.8 kg initial weight and recovered from hyperglycemia and hypertension after 23 weeks on a diet of whole grains, traditional Chinese medicinal foods and prebiotics. A decreased abundance of endotoxin biosynthetic genes in the gut of the volunteer was correlated with a decreased circulating endotoxin load and alleviated inflammation. Mono-association of germfree C57BL/6J mice with strain Enterobacter cloacae B29 isolated from the volunteer’s gut induced fully developed obesity and insulin resistance on a high-fat diet but not on normal chow diet, whereas the germfree control mice on a high-fat diet did not exhibit the same disease phenotypes. The Enterobacter-induced obese mice showed increased serum endotoxin load and aggravated inflammatory conditions. The obesity-inducing capacity of this human-derived endotoxin producer in gnotobiotic mice suggests that it may causatively contribute to the development of obesity in its human host.

Posted in General.

Tagged with diabetes, endotoxin, estrogen, inflammation, insulin resistance, lipopolysaccharide, LPS, obesity, Ray Peat, weight gain.

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By Team FPS – November 28, 2011

Fish Oil Toxicity

Also see:
PUFA, Fish Oil, and Alzheimers
Fish Oil and Lipid Peroxidation
The Randle Cycle
Women, Estrogen, and Circulating DHA
PUFA – Accumulation & Aging
Medium Chain Fats, Ketones, and Brain Function
PUFA, Development, and Allergy Incidence
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Commentary on Type 2 Diabetes
The Great Fish Oil Experiment – Ray Peat
Instead of helping, fish oil drives people towards a heart attack
Too Much of a Good(?) Thing: When Fish Oil Starts Clogging Your Arteries and Fattening Up Your Liver.

“Since the fish oils are commonly studied by comparing the supplemented animals with “control” animals receiving soy oil, corn oil, or safflower oil, which are strongly pro-inflammatory and broadly toxic, it isn’t surprising that their effects usually seem favorable. But when they are compared with saturated fats (as I mentioned in the “Fats and degeneration” newsletter) or with a fat free diet, their effects are seen to be pro-inflammatory and toxic.” -Ray Peat, PhD

The fish oil mega industry as we know it today began as the paint/varnish sector dried up when the petroleum industry took over that market. The fish oil industry had no other place to sell this waste product of fish production so they capitalized on the faulty research done by the Burrs’ in the late 1920s falsely showing essentiality for these fats (it was actually for seed oil fats truthfully but fish oils are the “new” “essential fats”). This misinterpreted research gave the seed and fish oil industry grounds to market these toxic fats as “health foods” for humans.

There is no such thing as “essential fatty acids“; the body doesn’t synthesize “essential” PUFA on its own b/c they are toxic, not because they are essential. One unsaturated fat the body does synthesize from sugar is the protective and anti-inflammatory Omega -9 Mead Acid, which is ironically a marker for “essential fatty acid” deficiency.

Today, the momentum and inertia behind these products is great because of repeated marketing efforts of these industries. The brainwashing is so good that both professionals and laypersons don’t consider taking a look at both the current and historical research about the negative effects of fish oil and other PUFA. We are now at a point of unheard of chronic disease in large part due to our shift away from saturated animal fats/coconut oil and an increase in plant-derived polyunsaturates from vegetables, beans, seed, nuts and fish oils.

Scientific Review of Fish Oils:
Why Fish Oil Fails: A Comprehensive 21st Century Lipids-Based Physiologic Analysis

Cancer Causing:
Cancer Res. 1998 Aug 1;58(15):3312-9.
Dietary omega-3 polyunsaturated fatty acids promote colon carcinoma metastasis in rat liver.
Griffini P, Fehres O, Klieverik L, Vogels IM, Tigchelaar W, Smorenburg SM, Van Noorden CJ.

Nutr Cancer. 1998;30(2):137-43.
Effects of dietary n-3-to-n-6 polyunsaturated fatty acid ratio on mammary carcinogenesis in rats.
Sasaki T, Kobayashi Y, Shimizu J, Wada M, In’nami S, Kanke Y, Takita T.

J Lipid Res. 2005 Jun;46(6):1278-84. Epub 2005 Mar 16.
Role of omega-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma.
Denkins Y, Kempf D, Ferniz M, Nileshwar S, Marchetti D.

Clin Exp Metastasis. 2000;18(5):371-7.
Promotion of colon cancer metastases in rat liver by fish oil diet is not due to reduced stroma formation.
Klieveri L, Fehres O, Griffini P, Van Noorden CJ, Frederiks WM.

Am. J. Epidemiol. (2011) doi: 10.1093/aje/kwr027
Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial
Theodore M. Brasky, Cathee Till, Emily White, Marian L. Neuhouser, Xiaoling Song, Phyllis Goodman, Ian M. Thompson, Irena B. King, Demetrius Albanes and Alan R. Kristal

Am J Clin Nutr. 2012 Dec;96(6):1354-61. doi: 10.3945/ajcn.112.034157. Epub 2012 Nov 7.
Fatty acid patterns and risk of prostate cancer in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition.
Dahm CC, Gorst-Rasmussen A, Crowe FL, Roswall N, Tjønneland A, Drogan D, Boeing H, Teucher B, Kaaks R, Adarakis G, Zylis D, Trichopoulou A, Fedirko V, Chajes V, Jenab M, Palli D, Pala V, Tumino R, Ricceri F, van Kranen H, Bueno-de-Mesquita HB, Quirós JR, Sánchez MJ, Luján-Barroso L, Larrañaga N, Chirlaque MD, Ardanaz E, Johansson M, Stattin P, Khaw KT, Wareham N, Wark PA, Norat T, Riboli E, Key TJ, Overvad K.

J Nutr. 2003 Nov;133(11):3664-9.
Fish intake is positively associated with breast cancer incidence rate.
Stripp C1, Overvad K, Christensen J, Thomsen BL, Olsen A, Møller S, Tjønneland A.

Immunosuppresion:
Transplantation. 1989 Jul;48(1):98-102.
Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for cyclosporine.
Kelley VE, Kirkman RL, Bastos M, Barrett LV, Strom TB.

Clin Immunol Immunopathol. 1991 Nov;61(2 Pt 1):161-76.
Immunosuppressive effects of fish oil in normal human volunteers: correlation with the in vitro effects of eicosapentanoic acid on human lymphocytes.
Virella G, Fourspring K, Hyman B, Haskill-Stroud R, Long L, Virella I, La Via M, Gross AJ, Lopes-Virella M.

Br J Nutr. 2003 Apr;89(4):523-31.
Influence of very low dietary intake of marine oil on some functional aspects of immune cells in healthy elderly people.
Bechoua S, Dubois M, Véricel E, Chapuy P, Lagarde M, Prigent AF.

Am J Clin Nutr. 2001 Mar;73(3):539-48.
Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y.
Thies F, Nebe-von-Caron G, Powell JR, Yaqoob P, Newsholme EA, Calder PC.

J Nutr. 2001 Jul;131(7):1918-27.
Dietary supplementation with gamma-linolenic acid or fish oil decreases T lymphocyte proliferation in healthy older humans.
Thies F, Nebe-von-Caron G, Powell JR, Yaqoob P, Newsholme EA, Calder PC.

J Cell Physiol. 2010 Nov;225(3):829-36.
Role of calcium and ROS in cell death induced by polyunsaturated fatty acids in murine thymocytes.
Prasad A, Bloom MS, Carpenter DO.

Impairment of mitochondrial function:
Proc Natl Acad Sci U S A. 1990 Nov;87(22):8845-9.
Incorporation of marine lipids into mitochondrial membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty acids.
Malis CD, Weber PC, Leaf A, Bonventre JV.

Int J Biochem Cell Biol. 2012 Sep;44(9):1569-73. Epub 2012 Jun 15.
Mitochondria: Omega-3 in the route of mitochondrial reactive oxygen species.
Al-Gubory KH.

Lipids. 2008 Sep;43(9):813-27. Epub 2008 Jul 10.
Dietary n-3 HUFA affects mitochondrial fatty acid beta-oxidation capacity and susceptibility to oxidative stress in Atlantic salmon.
Kjaer MA, Todorcević M, Torstensen BE, Vegusdal A, Ruyter B.

Increased lipid peroxidation:
Lipids. 1997 May;32(5):535-41.
Lipid peroxidation during n-3 fatty acid and vitamin E supplementation in humans.
Allard JP, Kurian R, Aghdassi E, Muggli R, Royall D.

Atherosclerosis. 2001 Mar;155(1):9-18.
Enhanced level of n-3 fatty acid in membrane phospholipids induces lipid peroxidation in rats fed dietary docosahexaenoic acid oil.
Song JH, Miyazawa T.

J Nutr. 1992 Nov;122(11):2190-5.
Lipid peroxidation products are elevated in fish oil diets even in the presence of added antioxidants.
Gonzalez MJ, Gray JI, Schemmel RA, Dugan L Jr, Welsch CW.

Nutrition. 2004 Feb;20(2):230-4.
Diets rich in saturated and polyunsaturated fatty acids: metabolic shifting and cardiac health.
Diniz YS, Cicogna AC, Padovani CR, Santana LS, Faine LA, Novelli EL.

Int J Biochem Cell Biol. 2012 Sep;44(9):1569-73. Epub 2012 Jun 15.
Mitochondria: Omega-3 in the route of mitochondrial reactive oxygen species.
Al-Gubory KH.

Cardiovascular Disease, Cancer, Mortality, No Benefit or Negative Results:
Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003177.
Omega 3 fatty acids for prevention and treatment of cardiovascular disease.
Hooper L, Thompson RL, Harrison RA, Summerbell CD, Moore H, Worthington HV, Durrington PN, Ness AR, Capps NE, Davey Smith G, Riemersma RA, Ebrahim SB.

Canadian Journal of Cardiology – 14 April 2014 (10.1016/j.cjca.2014.04.007)
“Fishing” for the origins of the “Eskimos and heart disease” story. Facts or wishful thinking? A review
George J. Fodor, Eftyhia Helis, Narges Yazdekhasti, Branislav Vohnout

Mitochondrion. 2011 Jan;11(1):97-103. doi: 10.1016/j.mito.2010.07.014. Epub 2010 Aug 5.
Dietary fatty acids and oxidative stress in the heart mitochondria.
Lemieux H, Bulteau AL, Friguet B, Tardif JC, Blier PU.

BMJ. 2006 Apr 1;332(7544):752-60. Epub 2006 Mar 24.
Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review.
Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA, Ebrahim SB, Davey Smith G.

Prog Lipid Res. 1995;34(3):199-217.
Fatty acid composition of adipose tissue in humans. Implications for the dietary fat-serum cholesterol-CHD issue.
Seidelin KN.

Atherosclerosis. 1990 Oct;84(2-3):229-37.
Fish oil produces an atherogenic lipid profile in hypertensive men.
Hughes GS, Ringer TV, Watts KC, DeLoof MJ, Francom SF, Spillers CR.

JAMA. 2012 Sep 12;308(10):1024-33.
Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.
Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS.

Toxic to the liver:
Gastroenterology. 1995 Aug;109(2):547-54.
Dietary saturated fatty acids: a novel treatment for alcoholic liver disease.
Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ.

Hepatology. 1997 Dec;26(6):1538-45.
Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat.
Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.

Alcohol. 2004 Aug;34(1):3-8.
Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium.
Purohit V1, Russo D, Coates PM.

J Pharmacol Exp Ther. 2001 Nov;299(2):638-44.
Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration.
Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.

Am J Physiol Gastrointest Liver Physiol. 2001 Dec;281(6):G1348-56.
Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines.
Nanji AA, Jokelainen K, Fotouhinia M, Rahemtulla A, Thomas P, Tipoe GL, Su GL, Dannenberg AJ.

J Pharmacol Exp Ther. 2001 Dec;299(3):832-9.
Arginine reverses ethanol-induced inflammatory and fibrotic changes in liver despite continued ethanol administration.
Nanji AA, Jokelainen K, Lau GK, Rahemtulla A, Tipoe GL, Polavarapu R, Lalani EN.

Cognitive Development, Mood, Depression, Quality of Life:
Prostaglandins Leukot Essent Fatty Acids. 1999 May-Jun;60(5-6):393-9.
Does high polyunsaturated free fatty acid level at the feto-maternal interface alter steroid hormone message during pregnancy?
Benassayag C, Rigourd V, Mignot TM, Hassid J, Leroy MJ, Robert B, Civel C, Grangé G, Dallot E, Tanguy J, Nunez EA, Ferré F.

Int Clin Psychopharmacol. 2006 Nov;21(6):319-36.
Fish oil and mental health: the role of n-3 long-chain polyunsaturated fatty acids in cognitive development and neurological disorders.
Assisi A, Banzi R, Buonocore C, Capasso F, Di Muzio V, Michelacci F, Renzo D, Tafuri G, Trotta F, Vitocolonna M, Garattini S.

Neurology. 2008 Aug 5;71(6):430-8.
Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial.
van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Dullemeijer C, Olderikkert MG, Beekman AT, de Groot CP.

Br J Nutr. 2008 Feb;99(2):421-31. Epub 2007 Oct 24.
No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial.
Rogers PJ, Appleton KM, Kessler D, Peters TJ, Gunnell D, Hayward RC, Heatherley SV, Christian LM, McNaughton SA, Ness AR.

Br J Nutr. 2012 Apr;107(8):1232-43. Epub 2011 Aug 25.
No effect of 12 weeks’ supplementation with 1 g DHA-rich or EPA-rich fish oil on cognitive function or mood in healthy young adults aged 18-35 years.
Jackson PA, Deary ME, Reay JL, Scholey AB, Kennedy DO.

Am J Clin Nutr. 2008 Sep;88(3):706-13.
Effect of fish-oil supplementation on mental well-being in older subjects: a randomized, double-blind, placebo-controlled trial.
van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Hoefnagels WH, Beekman AT, de Groot LC.

Neurotoxicol Teratol. 2010 Mar-Apr;32(2):171-81. Epub 2009 Oct 7.
Excess omega-3 fatty acid consumption by mothers during pregnancy and lactation caused shorter life span and abnormal ABRs in old adult offspring.
Church MW, Jen KL, Anumba JI, Jackson DA, Adams BR, Hotra JW.

J Am Geriatr Soc. 2009 Aug;57(8):1481-6. Epub 2009 Jun 22.
Effect of fish oil supplementation on quality of life in a general population of older Dutch subjects: a randomized, double-blind, placebo-controlled trial.
van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Olderikkert MG, Beekman AT, de Groot LC.

J Am Coll Nutr. 2009 Oct;28(5):525-42.
EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials.
Martins JG.

Glucose Metabolism:
Diabetes. 1989 Oct;38(10):1314-9.
Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM.
Borkman M, Chisholm DJ, Furler SM, Storlien LH, Kraegen EW, Simons LA, Chesterman CN.

Br J Nutr. 2003 Oct;90(4):777-86.
Fish-oil supplementation reduces stimulation of plasma glucose fluxes during exercise in untrained males.
Delarue J, Labarthe F, Cohen R.

Diabetes Care. 1990 Aug;13(8):821-9.
Effects of fish oil supplements in NIDDM subjects. Controlled study.
Hendra TJ, Britton ME, Roper DR, Wagaine-Twabwe D, Jeremy JY, Dandona P, Haines AP, Yudkin JS.

Atherosclerosis. 1991 Mar;87(1):65-73.
A controlled study on the effects of n-3 fatty acids on lipid and glucose metabolism in non-insulin-dependent diabetic patients.
Annuzzi G, Rivellese A, Capaldo B, Di Marino L, Iovine C, Marotta G, Riccardi G.

Eur J Clin Invest. 1992 Oct;22(10):645-50.
Supplementation with n-3 fatty acids reduces triglycerides but increases PAI-1 in non-insulin-dependent diabetes mellitus.
Boberg M, Pollare T, Siegbahn A, Vessby B.

J Intern Med. 1990 Aug;228(2):165-71.
Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulin-dependent diabetes mellitus.
Vessby B, Boberg M.

Brain Degeneration:
[Isoprostanes and neuroprostanes are inflammatory prostaglandin-like mediators (eicosanoids) formed from omega-3 PUFA fish oil (DHA/EPA).]

J Biol Chem. 1998 May 29;273(22):13605-12.
Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid.
Roberts LJ 2nd, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, Dettbarn WD, Morrow JD.

Free Radical Biology and Medicine
Volume 29, Issue 8, 15 October 2000, Pages 714-720
Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.
Mark A Lovell, Chengsong Xie, William R Markesbery

Ann Neurol. 1998 Sep;44(3):410-3.
Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer’s disease.
Montine TJ, Markesbery WR, Morrow JD, Roberts LJ 2nd.

J Neurochem. 1988 Apr;50(4):1185-93.
Induction of intracellular superoxide radical formation by arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures.
Chan PH, Chen SF, Yu AC.

Promotes Nitric Oxide and TNF:
J Surg Res. 1994 Jul;57(1):65-8.
Dietary fish oil enhances macrophage production of nitric oxide.
Chaet MS, Garcia VF, Arya G, Ziegler MM.

J Alzheimers Dis. 2003 Aug;5(4):315-22.
Omega-3 fatty acids and risk of cognitive impairment and dementia.
Laurin D, Verreault R, Lindsay J, Dewailly E, Holub BJ.

Brain Swelling:
J Neurochem. 1980 Oct;35(4):1004-7.
Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling.
Chan PH, Fishman RA.

Science. 1978 Jul 28;201(4353):358-60.
Brain edema: induction in cortical slices by polyunsaturated fatty acids.
Chan PH, Fishman RA.

J Neurochem. 1982 Feb;38(2):525-31.
Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices.
Chan PH, Yurko M, Fishman RA.

Neurotoxicology. 2007 Nov;28(6):1220-9. Epub 2007 Aug 10.
Detrimental effects of post-treatment with fatty acids on brain injury in ischemic rats.
Yang DY, Pan HC, Yen YJ, Wang CC, Chuang YH, Chen SY, Lin SY, Liao SL, Raung SL, Wu CW, Chou MC, Chiang AN, Chen CJ.

Increased Intestinal Permeability:
J Nutr. 2011 Sep;141(9):1635-42. Epub 2011 Jul 20.
Ingestion of (n-3) fatty acids augments basal and platelet activating factor-induced permeability to dextran in the rat mesenteric vascular bed.
Dombrowsky H, Lautenschläger I, Zehethofer N, Lindner B, Schultz H, Uhlig S, Frerichs I, Weiler N.

Lung Inflammation:
Nutrition. 2002 Jul-Aug;18(7-8):647-53.
Dietary fat composition alters pulmonary function in pigs.
Wolfe RR, Martini WZ, Irtun O, Hawkins HK, Barrow RE.

Slow Heart Rate:
Proc Natl Acad Sci U S A. 1994 October 11; 91(21): 9886–9890.
Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes.
J X Kang and A Leaf

Posted in General.

Tagged with Alzheimers, cancer, dementia, diabetes, EHA, EPA, fish oil toxicity, fish oils, free radicals, heart disease, hepatotoxicity, immunity, immunosuppression, inflammation, intestinal permeability, lipid peroxidation, lipid peroxides, liver, omega 3, PUFA, salmon, supplements, tuna.

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By Team FPS – November 26, 2011

Trauma & Resuscitation: Toxicity of Lactated Ringer’s Solution

Also see:
Resuscitation: Benefits of ATP, Glucose, and Sodium
Arachidonic Acid’s Role in Shock and Stress

Lactate increases blood viscosity, mimics stress, causes inflammation, and contributes to shock. Lactated Ringer’s solution contributes to the tissue damage caused by shock, when it’s used to resuscitate shock victims (Deree, et al., 2007, 2008): it contributes to the inflammatory processes associated with shock, unlike the use of hypertonic saline and other solutions. Lactate contributes to diabetes, inhibiting the ability to oxidize glucose. It promotes endothelial cell migration and leakiness, with increased vascular permeability factor (VPF or vascular endothelial growth factor, VEGF) (Nagy, et al. 1985): this can lead to breakdown of the “blood-brain barrier.” -Ray Peat, PhD

Lactated Ringer’s solution: A salt solution that has been used to increase blood volume in treating shock; the lactate was apparently chosen as a buffer in place of bicarbonate as a matter of convenience rather than physiology. This solution is toxic, partly because it contains the form of lactate produced by bacteria, but our own lactate, at higher concentrations, produces the same sorts of toxic effect, damaging mitochondria. Estrogenic phytotoxins damage mitochondria, kill brain cells; tofu is associated with dementia. -Ray Peat, PhD

When a person has an accident, or surgery, and goes into shock, the degree of lactic acidema is recognized as an indicator of the severity of the problem. Lactated Ringer’s solution has been commonly used to treat these people, to restore their blood pressure. But when prompt treatment with lactated Ringer’s solution has been compared with no early treatment at all, the patients who are not “rescuscitated” do better than those who got the early treatment. And when Ringer’s lactate has been compared with various other solutions, synthetic starch solutions, synthetic hemoglobin polymer solution, or simply a concentrated solution of sodium chloride, those who received the lactate solution did least well. For example, of 8 animals treated with another solution, 8 survived, while among 8 treated with Ringer’s lactate, 6 died. -Ray Peat, PhD

J Trauma. 1999 Apr;46(4):582-8; discussion 588-9.
Resuscitation with lactated Ringer’s solution in rats with hemorrhagic shock induces immediate apoptosis.
Deb S, Martin B, Sun L, Ruff P, Burris D, Rich N, DeBreux S, Austin B, Rhee P.
BACKGROUND:
We hypothesize that different resuscitative fluids may immediately affect the degree of apoptosis after hemorrhagic shock.
METHODS:
Rats (n = 35) were hemorrhaged 27 mL/kg over 5 minutes followed by 1 hour of shock, then resuscitation over 1 hour. The six treatment groups were sham hemorrhage, sham resuscitation, whole blood resuscitation, lactated Ringer’s solution (LR) resuscitation with three times the volume bled, sham hemorrhage with LR infusion, and 7.5% hypertonic saline resuscitation (9.7 mL/kg). Liver and small intestine were harvested immediately after resuscitation. Apoptosis was evaluated by using in situ cell death detection method.
RESULTS:
Resuscitation with LR resulted in a significant increase in small intestinal and liver apoptosis. Animals that received LR infusion without hemorrhage had an increased level of apoptosis in the intestine. Apoptosis in the intestine was observed in both the mucosa and muscularis externa. There was no increase in apoptosis in either organ in the animals resuscitated with sham resuscitation, whole blood, and hypertonic saline compared with the sham hemorrhage group.
CONCLUSION:
Resuscitation with LR solution after hemorrhagic shock increased immediate cell death by apoptosis in both the small intestine and liver. There was no significant increase in apoptosis in the animals resuscitated with hypertonic saline, whole blood, or in unresuscitated animals. Thus, the type of resuscitation fluid used may affect the apoptotic cellular response to shock.

Br J Anaesth. 2006 Oct;97(4):509-16. Epub 2006 Aug 16.
Comparison of lactated Ringer’s, gelatine and blood resuscitation on intestinal oxygen supply and mucosal tissue oxygen tension in haemorrhagic shock.
Knotzer H, Pajk W, Maier S, Dünser MW, Ulmer H, Schwarz B, Salak N, Hasibeder WR.
OBJECTIVES:
To evaluate the effects on intestinal oxygen supply, and mucosal tissue oxygen tension during haemorrhage and after fluid resuscitation with either blood (B; n=7), gelatine (G; n=8), or lactated Ringer’s solution (R; n=8) in an autoperfused, innervated jejunal segment in anaesthetized pigs.
METHODS:
To induce haemorrhagic shock, 50% of calculated blood volume was withdrawn. Systemic haemodynamics, mesenteric venous and systemic acid-base and blood gas variables, and lactate measurements were recorded. A flowmeter was used for measuring mesenteric arterial blood flow. Mucosal tissue oxygen tension (PO(2)muc), jejunal microvascular haemoglobin oxygen saturation (HbO(2)) and microvascular blood flow were measured. Measurements were performed at baseline, after haemorrhage and at four 20 min intervals after fluid resuscitation. After haemorrhage, animals were retransfused with blood, gelatine or lactated Ringer’s solution until baseline pulmonary capillary wedge pressure was reached.
RESULTS:
After resuscitation, no significant differences in macrohaemodynamic parameters were observed between groups. Systemic and intestinal lactate concentration was significantly increased in animals receiving lactated Ringer’s solution [5.6 (1.1) vs 3.3 (1.1) mmol litre(-1); 5.6 (1.1) vs 3.3 (1.2) mmol litre(-1)]. Oxygen supply to the intestine was impaired in animals receiving lactated Ringer’s solution when compared with animals receiving blood. Blood and gelatine resuscitation resulted in higher HbO(2) than with lactated Ringer’s resuscitation after haemorrhagic shock [B, 43.8 (10.4)%; G, 34.6 (9.4)%; R, 28.0 (9.3)%]. PO(2)muc was better preserved with gelatine resuscitation when compared with lactated Ringer’s or blood resuscitation [20.0 (8.8) vs 13.8 (7.1) mm Hg, 15.2 (7.2) mm Hg, respectively].
CONCLUSION:
Blood or gelatine infusion improves mucosal tissue oxygenation of the porcine jejunum after severe haemorrhage when compared with lactated Ringer’s solution.

J Surg Res. 2007 Nov;143(1):99-108.
Pentoxifylline attenuates lung injury and modulates transcription factor activity in hemorrhagic shock.
Deree J, Martins J, de Campos T, Putnam JG, Loomis WH, Wolf P, Coimbra R.
BACKGROUND:
Evidence exists that resuscitation with Ringer’s lactate (RL) contributes to postshock inflammation and lung injury. We hypothesized that the anti-inflammatory agent pentoxifylline (PTX) attenuates postresuscitative lung injury through modulation of transcription factors after hemorrhagic shock.
METHODS:
Male Sprague Dawley rats underwent a 1 h period of hypotension and resuscitation with RL (32 mL/kg) or RL + PTX (25 mg/kg). Lung sections were graded for histological injury and myeloperoxidase content. Cytokine-induced neutrophil chemoattractant concentration was determined by enzyme immunoassay. Matrix metalloproteinase-2 and -9 (MMP) activity was evaluated by zymography. Heme oxygenase-1, nuclear factor kappa B (NF-kappaB) p65 nuclear translocation, and cytoplasmic I-kappaB phosphorylation were assessed by Western blot. NF-kappaB and cAMP response element binding protein (CREB) DNA binding were determined by light shift chemiluminescent electrophoretic mobility shift assay.
RESULTS:
RL resuscitation led to statistically significant increases in all parameters of lung injury when compared with the negative control. The addition of PTX significantly decreased histology lung injury, myeloperoxidase content, cytokine-induced neutrophil chemoattractant by 48% (P < 0.05), heme oxygenase-1 expression by 50% (P < 0.05), MMP-2 activity by 70% (P < 0.05), MMP-9 activity by 44% (P < 0.05), cytoplasmic I-kappaB phosphorylation by 66% (P < 0.01), nuclear NF-kappaB p65 phosphorylation by 51% (P < 0.05), and NF-kappaB DNA binding by 42% (P < 0.05). In contrast, PTX increased CREB DNA binding by 69% when compared with RL alone (P < 0.04).
CONCLUSIONS:
The addition of PTX to conventional RL infusion after shock significantly reduced histological lung injury and pulmonary neutrophil activity when compared to treatment with RL alone. The administration of PTX was also associated with diminished NF-kappaB and enhanced CREB activation. Therefore, the administration of PTX may serve as a novel therapeutic adjunct after hemorrhagic shock.

J Trauma. 2007 Apr;62(4):818-27; discussion 827-8.
Hypertonic saline and pentoxifylline attenuates gut injury after hemorrhagic shock: the kinder, gentler resuscitation.
Deree J, de Campos T, Shenvi E, Loomis WH, Hoyt DB, Coimbra R.
BACKGROUND:
We have previously demonstrated that postshock resuscitation with Hypertonic saline and Pentoxifylline (HSPTX) attenuates pulmonary and histologic gut injury when compared with Ringer’s lactate (RL). In this study, we hypothesized that the decrease in gut injury observed with HSPTX is associated with the attenuation of inducible nitric oxide synthase (iNOS) activity and production of ileal proinflammatory mediators after hemorrhagic shock.
METHODS:
In a rat model of hemorrhagic shock, resuscitation was conducted with RL (32 mL/kg; n = 7) or HSPTX (4 mL/kg 7.5% NaCl + PTX 25 mg/kg; n = 7). Sham animals that did not undergo shock were also studied. Four hours after resuscitation, the terminal ileum was collected for evaluation of nitrite, tumor necrosis factor (TNF)-alpha, Interleukin (IL)-6, and cytokine-induced neutrophil chemoattractant (CINC) by enzyme immunoassay. Heme oxygenase-1 (HO-1), iNOS, cytoplasmic inhibitor of kappa B (Ikappa B) phosphorylation, and nuclear factor (NF)kappa B p65 nuclear translocation were determined by Western blot.
RESULTS:
HSPTX resuscitation resulted in a 49% decrease in iNOS when compared with RL (p < 0.05). Similar results were obtained when examining nitrite (882 +/- 59 vs. 1,435 +/- 177 micromol/L; p < 0.01), and HO-1 content (p < 0.05). RL resuscitation resulted in markedly higher levels of TNF-alpha (83 +/- 27 vs. 9 +/- 5 pg/mL; p < 0.01), IL-6 (329 +/- 58 vs. 118 +/- 43 pg/mL; p < 0.05), and CINC (0.43 +/- .06 vs. 0.19 +/- .08 ng/mL; p < 0.05) than HSPTX. The increase in cytokines observed with RL was also associated with an increase in I-kappaB phosphorylation (p < 0.01) and NF-kappaB p65 nuclear translocation (p < 0.001).
CONCLUSION:
The attenuation in gut injury after postshock resuscitation with HSPTX is associated with downregulation of iNOS activity and subsequent proinflammatory mediator synthesis. HSPTX has the potential to be a superior resuscitation fluid with significant immunomodulatory properties.

J Trauma. 2007 Jan;62(1):104-11.
Hypertonic saline and pentoxifylline reduces hemorrhagic shock resuscitation-induced pulmonary inflammation through attenuation of neutrophil degranulation and proinflammatory mediator synthesis.
Deree J, Martins JO, Leedom A, Lamon B, Putnam J, de Campos T, Hoyt DB, Wolf P, Coimbra R.
BACKGROUND:
Ringer’s lactate (RL), the current standard resuscitation fluid, potentiates neutrophil activation and is associated with pulmonary inflammation. Resuscitation with hypertonic saline and pentoxifylline (HSPTX) has been shown to attenuate hemorrhagic shock-induced injury when compared with RL. Because the neutrophil plays a major role in postshock inflammation, we hypothesized that HSPTX reduces pulmonary inflammation after resuscitation in comparison to RL.
METHODS:
Sprague-Dawley rats underwent controlled shock and were resuscitated with RL (32 mL/kg) or HSPTX (4 mL/kg 7.5% NaCl + pentoxifylline 25 mg/kg). Animals who did not undergo shock or resuscitation served as controls. After 24 hours, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. Cytokine induced neutrophil chemoattractant (CINC) was measured in BALF by enzyme-linked immunosorbent assay. Matrix metalloproteinases (MMP)-2 and -9 were measured by zymography. Hemeoxygenase-1 (HO-1) was assessed by Western blot and immunohistochemistry.
RESULTS:
HSPTX resuscitation led to a 62% decrease in CINC levels compared with RL (p < 0.01). BALF MMP-2 expression was attenuated by 11% with HSPTX (p = 0.09). Lung MMP-2 and MMP-9 expression was reduced by 89% (p < 0.01) and 76%, respectively (p < 0.05). Lung HO-1 expression declined by 34% with HSPTX in comparison to RL (p < 0.01), indicating less oxidative injury. Lung immunohistochemistry localized HO-1 to neutrophils, macrophages, and airway epithelial cells.
CONCLUSION:
Collectively, the attenuation of pulmonary inflammation with HSPTX after shock when compared with RL is associated with downregulation of neutrophil activation, oxidative stress, and proinflammatory mediator production.

J Trauma. 2008 May;64(5):1230-8; discussion 1238-9.
Hepatic transcription factor activation and proinflammatory mediator production is attenuated by hypertonic saline and pentoxifylline resuscitation after hemorrhagic shock.
Deree J, Loomis WH, Wolf P, Coimbra R.
BACKGROUND:
Fluid resuscitation can contribute to postshock inflammation and the development of end organ injury. We have previously observed an attenuation in pulmonary and ileal inflammation when hypertonic saline and pentoxifylline (HSPTX) were concomitantly administered after hemorrhage. We hypothesized that the attenuation in hepatic injury observed with HSPTX is associated with the reduction of transcription factor activation and proinflammatory mediator production when compared with Ringer’s lactate (RL).
METHODS:
Male Sprague-Dawley rats were resuscitated with racemic RL (32 mL/kg) or HSPTX (4 mL/kg 7.5% NaCl + PTX 25 mg/kg) and killed at 4 hours and 24 hours after resuscitation. Liver injury was determined by histology and serum aminotransferases. Nitrite, tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 were measured with enzyme-linked immunosorbent assay. High mobility group box 1, inducible nitric oxide synthase, nuclear factor (NF)-kappaB phosphorylation, and signal transducers and activators of transcription-3 phosphorylation were determined by Western blot. Transcription factor activation was verified with Electrophoretic Mobility Shift Assay.
RESULTS:
RL resuscitation led to significant increases all measured parameters when compared with control. In contrast, HSPTX did not induce elevations in histologic liver injury or alanine aminotransferase levels. HSPTX attenuated inducible nitric oxide synthase by 23% (p < 0.01), nitrite by 25% (p < 0.05), tumor necrosis factor-alpha by 25% (p < 0.05), IL-1 by 63% (p < 0.01), IL-6 by 35% (p < 0.05), and high mobility group box 1 by 39% (p < 0.05) when compared with RL. HSPTX reduced IkappaB-alpha phosphorylation by 34% (p < 0.05), NF-kappaB p65 phosphorylation by 75% (p < 0.01), and signal transducers and activators of transcription-3 phosphorylation by 52% (p < 0.01).
CONCLUSIONS:
The reduction in liver injury observed with HSPTX resuscitation after hemorrhage is associated with attenuation transcription factor activation and proinflammatory mediators. HSPTX has the potential to be a superior resuscitation fluid with significant immunomodulatory properties.

Anesth Analg. 1996 Oct;83(4):782-8.
Small-volume resuscitation using hypertonic saline improves organ perfusion in burned rats.
Kien ND, Antognini JF, Reilly DA, Moore PG.
Resuscitation using small volumes (3-5 mL/kg) of 7.5% hypertonic saline (HTS) is effective for hemorrhagic shock. Whether HTS is beneficial for the initial resuscitation of burn injury is not clear. We compared the hemodynamic effects of HTS versus lactated Ringer’s solution (LR) and examined organ tissue perfusion during burn resuscitation (R). Full thickness scald burn (35% of total body surface area) was induced in pentobarbital-anesthetized rats. Regional blood flows were measured using radioactive microspheres before and 30 min after burn, and after R with either HTS (4 mL/kg) or LR (at a dose required for equivalent restoration of arterial blood pressure). Data from the HTS-or LR-resuscitated groups were compared to those from a nonresuscitated group (n = 10 in each group). Mean arterial pressure decreased 30% after burn (from 120 +/- 4 to 84 +/- 5 mm Hg, mean +/- SEM) and returned toward baseline (112 +/- 7 mm Hg) at 10 min after R with HTS (4 mL/kg) or LR (22.6 +/- 0.7 mL/kg), but subsequently decreased to 100 +/- 7 mm Hg with HTS and 105 +/- 5 mm Hg with LR at 30 min. In contrast to LR, resuscitation using HTS was associated with tachycardia. Blood flows to the skin and muscle of the normal or burn regions did not change after fluid resuscitation as compared to a nonresuscitated group. Fluid resuscitation transiently increased intestinal perfusion. Similar improvements in blood flow to the spleen were observed with HTS and LR at 10 min after R (from 128 +/- 10 to 156 +/- 15 and from 113 +/- 10 to 145 +/- 26 mL.min-1 x 100 g-1, respectively). However, at 30 min after R, splenic perfusion in the LR group was not different from that in the nonresuscitated group. Blood flows to the brain and kidney increased 39% and 42%, respectively, with HTS. HTS was also associated with pronounced improvements in blood flows to the heart (from 346 +/- 20 to 631 +/- 37 mL.min-1 x 100 g-1), liver (from 36 +/- 2 to 62 +/- 4 mL.min-1 x 100 g-1), and testis (from 29 +/- 2 to 43 +/- 2 mL.min-1 x 100g-1). Resuscitation using HTS was associated with rapid improvement in organ tissue perfusion in anesthetized rats subjected to burn injury. In comparison to LR, greater increases in blood flows to the heart, kidney, liver, and testis were observed with HTS. The results suggest that significant improvement in blood flow distribution can be achieved using HTS at less than one fifth the volume of LR for the initial treatment of burn shock.

Carbon dioxide and oxygen mixture (7% CO2, 93% O2) improves survival in rats with cardiac arrest.

Resuscitation. 1986 Apr;13(3):165-73.
The effect of carbon dioxide, lidoflazine and deferoxamine upon long term survival following cardiorespiratory arrest in rats.
Badylak SF, Babbs CF.
This study examined the effect of carbon dioxide, lidoflazine and deferoxamine therapy upon the 10-day survival incidence and subsequent neurologic function of rats subjected to 7 min of cardiorespiratory arrest with resuscitation. Cardiac arrest (asystole) was induced at time zero by injection of cold, 1% KCl into the left ventricle of ketamine-anesthetized rats pretreated with succinylcholine. Positive pressure ventilation was discontinued at time zero. Cardiopulmonary resuscitation (CPR) was begun at 7 min, and animals with return of spontaneous circulation were entered into the study. Twenty treated rats were ventilated for 1 h with 7% carbon dioxide-93% oxygen and given lidoflazine (2.0 mg/kg, i.v.) and deferoxamine (50 mg/kg, i.v.) 5 min after CPR. Twenty control rats were ventilated for 1 h with 100% oxygen and given lidoflazine vehicle and deferoxamine vehicle. Lidoflazine treatment (1.0 mg/kg) for the treated group, or lidoflazine vehicle for the control group, was repeated at 8 h postresuscitation. At 2 days postresuscitation, 75% of treated rats vs. 25% of control rats were alive (CHI2 = 10.0, d.f. = 1, P less than 0.01), and at 10 days, 60% of treated rats vs. 25% of control rats were alive (CHI2 = 5.01, d.f. = 1, P less than 0.05). There was no detectable neurologic deficit among survivors in either group at 15 days. The combination of carbon dioxide, lidoflazine and deferoxamine, administered after return of spontaneous circulation, is a simple and easily administered treatment regimen that improves the survival incidence without neurologic deficits in this animal model of cardiorespiratory arrest and CPR.

Cell Cycle. 2010 Sep 1;9(17):3506-14. Epub 2010 Sep 21.
Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism.
Bonuccelli G1, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, Frank PG, Flomenberg N, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP.
Previously, we proposed a new model for understanding the “Warburg effect” in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm “The Reverse Warburg Effect.” Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ∼2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ∼10-fold. Thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the “Reverse Warburg Effect”. Moreover, we discuss the possibility that it may be unwise to use lactate-containing i.v. solutions (such as Lactated Ringer’s or Hartmann’s solution) in cancer patients, given the dramatic metastasis-promoting properties of L-lactate. Also, we provide evidence for the up-regulation of oxidative mitochondrial metabolism and the TCA cycle in human breast cancer cells in vivo, via an informatics analysis of the existing raw transcriptional profiles of epithelial breast cancer cells and adjacent stromal cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue.

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Tagged with cancer, carbon dioxide, fermented food, glycolysis, kefir, kombucha, lactate, lactic acid, Resuscitation, ringer's solution, saline, salt, Sauerkraut, sodium, trauma, yogurt.

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By Team FPS – November 22, 2011

PUFA Promote Cancer

Also see:
Toxicity of Stored PUFA
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
PUFA Accumulation & Aging
Maternal PUFA Intake Increases Breast Cancer Risk in Female Offspring
Israeli Paradox: High Omega -6 Diet Promotes Disease
Benefits of Aspirin
Arachidonic Acid’s Role in Stress and Shock
Most cancer cases due to lifestyle choices, not ‘bad luck,’ study suggests

“After presenting overwhelming evidence that thyroid deficiency is the culprit in antherosclerosis, the final chapter urges the abandonment of polyunsaturated fats in our diet. In both experimental animals and man, in addition to toxic symptoms, a rise in cancer has been reported after prolonged ingestion of polyunsaturated fats.” -Broda Barnes, MD, PhD (Solved the Riddle of Heart Attacks)

“Be very careful with the unsaturated oils, such as safflower, corn, and cod liver oil: they destroy vitamin E and can cause cancer.” -Ray Peat, PhD

“In 1927, German researchers reported that a fat-free diet prevented the occurrence of spontaneous cancers in rats . Since, a little later, other workers found that the elimination of unsaturated fats from the diet not only prevented cancer, but also caused a large increase in the metabolic rate, it might have been possible to conclude that it is not living which kills us, but something in the environment. Some people did draw that conclusion, but research funds go mainly to product-oriented research, and “the environment” has been hard to package as a product.” -Ray Peat, PhD

“Cancer can’t occur, unless there are unsaturated oils in the diet. [C. Ip, et al., Cancer Res. 45, 1985.]” -Ray Peat, PhD

“The absence of cancer on a diet lacking unsaturated fats, the increased rate of metabolism, decreased free radical production, resistance to stress and poisoning by iron, alcohol, endotoxin, alloxan and streptozotocin, etc., improvement of brain structure and function, decreased susceptibility to blood clots, and lack of obesity and age pigment on a diet using coconut oil rather than unsaturated fats, indicates that something very simple can be done to reduce the suffering from the major degenerative diseases, and that it is very likely acting by reducing the aging process itself at its physiological core.” -Ray Peat, PhD

“There are many people currently recommending fish oil (or other highly unsaturated oils) for preventing or treating cancer, and it has become almost as common to recommend a sugar free diet, “because sugar feeds cancer.” This is often, incorrectly, said to be the meaning of Warburg’s demonstration that cancer cells have a respiratory defect that causes them to produce lactic acid from glucose even in the presence of oxygen. Cancer cells use glucose and the amino acid glutamine primarily for synthetic purposes, and use fats as their energy source;the growth stimulating effect of the “essential fatty acids” (Sueyoshi and Nagao, 1962a; Holley, et al., 1974) shows that depriving a tumor of those fats retards its growth. The great energetic inefficiency of the cancer metabolism, which causes it to produce a large amount of heat and to cause systemic stress, failure of immunity, and weight loss, is because it synthesizes fat from glucose and amino acids, and then oxidizes the fat as if it were diabetic.” -Ray Peat, PhD

“If the cancer-productive field is taken into account, all of the factors that promote and sustain that field should be considered during therapy.

Two ubiquitous carcinogenic factors that can be manipulated without toxins are the polyunsaturated fatty acids (PUFA) and estrogen. These closely interact with each other, and there are many ways in which they can be modulated.

For example, keeping cells in a well oxygenated state with thyroid hormone and carbon dioxide will shift the balance from estradiol toward the weaker estrone. The thyroid stimulation will cause the liver to excrete estrogen more quickly, and will help to prevent the formation of aromatase in the tissues. Low temperature is one of the factors that increases the formation of estrogen. Lactic acid, serotonin, nitric oxide, prostaglandins, and the endorphins will be decreased by the shift toward efficient oxidative metabolism.

Progesterone synthesis will be increased by the higher metabolic rate, and will tend to keep the temperature higher.

Thyroid hormone, by causing a shift away from estrogen and serotonin, lowers prolactin, which is involved in the promotion of several kinds of cancer.

Vitamin D and vitamin K have some antiestrogenic effects. Vitamin D and calcium lower the inflammation-promoting parathyroid hormone (PTH).

Eliminating polyunsaturated fats from the diet is essential if the bystander effect is eventually to be restrained. Aspirin and salicylic acid can block many of the carcinogenic effects of the PUFA. Saturated fats have a variety of antiinflammatory and anticancer actions. Some of those effects are direct, others are the result of blocking the toxic effects of the PUFA. Keeping the stored unsaturated fats from circulating in the blood is helpful, since it takes years to eliminate them from the tissues after the diet has changed. Niacinamide inhibits lipolysis. Avoiding over-production of lipolytic adrenaline requires adequate thyroid hormone, and the adjustment of the diet to minimize fluctuations of blood sugar.” -Ray Peat, PhD

Cancer Res. 1985 May;45(5):1997-2001.
Requirement of essential fatty acid for mammary tumorigenesis in the rat.
Ip C, Carter CA, Ip MM.
In an attempt to determine the requirement of essential fatty acid for dimethylbenz(a)anthracene-induced mammary tumorigenesis, rats were fed diets containing different levels of linoleate: 0.5, 1.1, 1.7, 2.2, 3.5, 4.4, 8.5, or 11.5%. Each diet contained 20% of fat by weight, with varying amounts of coconut oil and corn oil added to achieve the desired levels of linoleate. Mammary tumorigenesis was very sensitive to linoleate intake and increased proportionately in the range of 0.5 to 4.4% of dietary linoleate. Regression analysis indicated that a breakpoint occurred at 4.4%, beyond which there was a very poor linear relationship, suggesting the possibility of a plateau. From the intersection of the regression lines in both the upper and lower ranges, the level of linoleate required to elicit the maximal tumorigenic response was estimated to be around 4%. The differences in tumor yield could not be correlated with changes in prostaglandin E concentration in the mammary fat pads of normal animals maintained on similar diets, suggesting that linoleate may act by some other mechanism to stimulate mammary tumorigenesis.

Nutrition Research
Volume 12, Issue 6, June 1992, Pages 767-772
Effect of low level flaxseed suplementation on the fatty acid composition of mammary glands and tumors in rats
Maria R. Serraino Ph.D., Lilian U. Thompson Ph.D., Stephen C. Cunnane Ph.D.
The high alpha-linolenic acid (ALA; C18:3n-3) content of flaxseed oil and the observed protective effects of omega-3 fatty acids on cancer have led to the hypothesis that the fatty acid composition of flaxseed may render it protective against cancer. Previous studies have suggested that supplementation of a basal high-fat diet with flaxseed flour (FF) at the 5% level may influence the risk for mammary carcinogenesis but it is unknown whether the fatty acid composition of its oil (1.9% in the diet) contributed to this effect. This study showed that feeding 5% FF significantly increased the ALA and decreased the C22:5n-6 contents of the mammary glands and tumors of carcinogen-treated rats and the mammary gland of the non-carcinogen treated rats. There were small but insignificant effects on the endogenously synthesized long chain fatty acids (e.g. 16:0, 16:1n-7, 18:0 and 18:1n-9) and the longer chain unsaturated fatty acids (e.g. 20:5n-3 and 22:6n-3) derived as a result of chain elongation and desaturation of ALA. The results suggest that the fatty acid composition of the mammary tissues and tumors may be affected even at low level of flaxseed oil, and that this oil may have a role in the observed effect of flaxseed on tumorigenesis. Further studies are required to explore this possibility.

In Vivo. 1998 Nov-Dec;12(6):675-89.
Comparative anticancer effects of vaccination and dietary factors on experimentally-induced cancers.
Zusman I.
The role of two major factors were analyzed in the prevention of experimentally-induced cancers: a) vaccination of animals with polyclonal IgG generated against the soluble p53 antigen and b) feeding of animals with diets rich with dietary fibers or fat. a) In vaccination, a few attempts have been made to utilize p53 protein as a tumor suppressor. IgG generated against the cytoplasmic, soluble p53 antigen from tumor-bearing rats prevents the carcinogenic effect of 1,2-dimethylhydrazine (DMH) decreasing significantly the number of tumor-bearing rats in vaccinated group compared with non vaccinated controls and preventing benign tumors from becoming malignant. The antitumor effect of vaccination is accompanied by a significant increase in the serum-level of p53 antigen in vaccinated rats compared with non vaccinated controls. The immune response of a host to vaccination activates the lymph components of the spleen, and this activation is manifested by the multiplication of the number of lymphocytes which are generated against specific antigens. This multiplication is achieved by the higher division of the antigen-specific lymphoblasts with their subsequent transformation into plasma cells. These cells synthesize the specific protein (IgG). One such protein is the tumor-associated p53 protein, which is synthesized by rats against rabbit anti-p53 IgG. b) The role of dietary factors in the prevention of chemically induced cancer was reviewed on two models: the role of high fiber diets in prevention of colon cancer, and the role of high fat diets in the prevention of mammary gland cancer. Experiments in colon cancer showed that 20% cellulose decreased significantly tumor incidence caused by DMH. The tumor-preventive effect of a cellulose diet was accompanied by increased enzyme concentrations, such as ornithine decarboxylase, thymidine kinase and beta-glucuronidase. This effect was accompanied by activation of some cellular mechanisms, i.e. apoptosis, proliferating cell nuclear antigen (PCNA) and p53 protein synthesis. Experiments in mammary glands cancer showed that a 15% olive-oil diet reduced significantly the tumor incidence caused by 9,10-dimethyl-1,2-benzanthracene. The antitumor effect of the olive-oil diet was connected to its content of monounsaturated fatty acids, such as oleic and palmitic acids. The promotive tumorigenic effects of other high-fat diets (avocado, soybeans) were associated with high content of some polyunsaturated fatty acids (linoleic and alpha-linolenic). Different diets have different targets. The effect of the same diet depends on its anti-tumor substances content. CONCLUSIONS: Vaccination and some diets have similar mechanism in their tumor-preventive effects.

Am J Clin Nutr. 1991 Apr;53(4 Suppl):1064S-1067S.
Dietary fats and cancer.
Carroll KK.
Evidence relating dietary fat to cancer at sites such as the breast and colon is provided by experiments showing that animals fed high-fat diets develop cancer at these sites more readily than do animals fed low-fat diets and by epidemiological data from different countries showing strong positive correlations between cancer incidence and mortality, and level of dietary fat. Experiments on animals have indicated that polyunsaturated vegetable oils promote cancer more effectively than do saturated fats or polyunsaturated fish oils, whereas in the epidemiological data, total dietary fat correlates with cancer incidence and mortality at least as well as does any particular type of fat. Case-control and cohort studies have not shown strong indications of a relationship between dietary fat and cancer, perhaps because of methodological difficulties inherent in such studies. The weight of evidence continues to indicate that long-term adherence to a low-fat diet can reduce the risk of some common types of cancer.

Cancer Res. 1998 Aug 1;58(15):3312-9.
Dietary omega-3 polyunsaturated fatty acids promote colon carcinoma metastasis in rat liver.
Griffini P, Fehres O, Klieverik L, Vogels IM, Tigchelaar W, Smorenburg SM, Van Noorden CJ.
The effects of omega-3 polyunsaturated fatty acids (PUFAs) and omega-6 PUFAs on the development of experimentally induced colon carcinoma metastasis in rat liver were investigated quantitatively in vivo. Rats were kept on either a low-fat diet or on a fish oil (omega-3 PUFAs) or safflower oil (omega-6 PUFAs) diet for 3 weeks before the administration of colon cancer cells to the portal vein, until they were sacrificed at 1 or 3 weeks after tumor transplantation. At 1 week after transplantation, the fish oil diet had induced 7-fold more metastases (in terms of number and size) than had the low-fat diet, whereas the safflower oil diet had not affected the number and total volume of metastases. At 3 weeks after tumor transplantation, the fish oil diet and the safflower oil diet had induced, respectively, 10- and 4-fold more metastases (number) and over 1000- and 500-fold more metastases (size) than were found in the livers of rats on the low-fat diet. These differences were sex independent. Immunohistochemical analysis revealed that the immune system in the liver (Kupffer cells, pit cells, T cells, newly recruited macrophages, and the activation state of macrophages) did not play a significant role in this diet-dependent outgrowth of tumors. In conclusion, omega-3 and omega-6 PUFAs promote colon cancer metastasis in the liver without down-regulating the immune system. This finding has serious implications for the treatment of cancer patients with fish oil diet to fight cachexia.

Lipids. 1987 Jun;22(6):445-54.
Effects of fatty acids on gap junctional communication: possible role in tumor promotion by dietary fat.
Aylsworth CF, Welsch CW, Kabara JJ, Trosko JE.
Dietary lipids, in particular unsaturated fat, promote the development of many experimental tumors. However, no mechanisms to fully explain these effects have been elucidated. Recent reports, which we summarize here, suggest a role for gap junction-mediated intercellular communication in the process of tumor promotion. We also review tumor-promoting effects of dietary fat on experimental, particularly mammary, carcinogenesis. Our main focus is to review recent data examining the inhibitory effects of unsaturated fatty acids on metabolic cooperation in Chinese hamster V79 cells. These data suggest that inhibition of junctional communication may be involved mechanistically in the promotion of tumors by high levels of dietary unsaturated fat. Finally, potential mechanisms by which unsaturated fatty acids inhibit metabolic cooperation are examined.

Nutr Cancer. 1984;6(2):77-85.
Enhancement of 1,2-dimethylhydrazine-induced large bowel tumorigenesis in Balb/c mice by corn, soybean, and wheat brans.
Clapp NK, Henke MA, London JF, Shock TL.
This study was designed to determine the effects of four well-characterized dietary brans on large bowel tumorigenesis induced in mice with 1,2-dimethylhydrazine (DMH). Eight-week-old barrier-derived male Balb/c mice were fed a semisynthetic diet with 20% bran added (either corn, soybean, soft winter wheat, or hard spring wheat) or a no-fiber-added control diet. Half of each group was given DMH (20 mg/kg body weight/week, subcutaneously for 10 weeks) beginning at 11 weeks of age. Surviving mice were killed 40 weeks after the first DMH injection. Tumors were not found in mice not subjected to DMH. In DMH-treated mice, tumors were found almost exclusively in the distal colon. Tumor incidences were as follows: controls, 11%; soybean group, 44%; soft winter wheat group, 48%; hard spring wheat group, 58%; and corn group, 72%. Tumors per tumor-bearing mouse ranged from 1.4 to 1.6, except in the corn group, which had 2.1. A positive correlation was found between percentage of neutral detergent fiber in the brans and tumor incidences but not between the individual components of cellulose, hemicellulose, or lignin. The enhancement of DMH-induced large bowel tumorigenesis by all four bran types may reflect a species and/or mouse strain effect that is bran-source related. These data emphasize the importance of using well-defined bran in all “fiber” studies.

Lipids. 1987 Jun;22(6):455-61.
The influence of dietary medium chain triglycerides on rat mammary tumor development.
Cohen LA, Thompson DO.
The N-nitrosomethylurea rat mammary tumor model was used to compare the tumor-promoting effects of a high-fat (HF) diet containing a 3:1 mixture of medium chain triglycerides (MCT) and corn oil with that of a HF and a low-fat (LF) corn oil diet. The serum and tumor lipid content and fatty acid (FA) composition were also determined in the three dietary groups. It was found that the MCT-containing diet failed to promote tumor development compared with the HF corn oil group. Tumor incidence in the HF-MCT group was similar to that of the LF corn oil group (5% fat, w/w), but significantly decreased compared to the HF corn oil group. Total serum cholesterol levels were significantly depressed in the HF corn oil group compared to the HF-MCT and LF corn oil groups. Analysis of serum and tumor FA profiles indicated that the HF corn oil group exhibited approximately twice the amount of linoleic acid (LA) as the other two treatment groups. Differences among the three groups in the major FA metabolite of LA, arachidonic acid, were minimal. These results are consistent with the hypothesis that tumor promotion by dietary fat is more a function of the type than the amount of fat ingested. In addition, they indicate that MCT, due at least in part to their unique structural and physiological properties, exert markedly different effects on mammary tumor development than conventional long chain unsaturated fatty acids.

Arch Intern Med. 1998 Jan 12;158(1):41-5.
A prospective study of association of monounsaturated fat and other types of fat with risk of breast cancer.
Wolk A, Bergström R, Hunter D, Willett W, Ljung H, Holmberg L, Bergkvist L, Bruce A, Adami HO.
BACKGROUND:
Animal studies suggest that monounsaturated and polyunsaturated fat may have opposite effects on the risk of breast cancer.
METHODS:
We performed a population-based prospective cohort study, including 61,471 women aged 40 to 76 years from 2 counties in central Sweden who did not have any previous diagnosis of cancer; 674 cases of invasive breast cancer occurred during an average follow-up of 4.2 years. All subjects answered a validated 67-item food frequency questionnaire at baseline. Cox proportional hazards models were used to obtain adjusted rate ratio (RR) estimates with 95% confidence intervals (CIs).
RESULTS:
After mutual adjustment of different types of fat, an inverse association with monounsaturated fat and a positive association with polyunsaturated fat were found. The RR for each 10-g increment in daily intake of monounsaturated fat was 0.45 (95% CI, 0.22-0.95), whereas the RR for a 5-g increment of polyunsaturated fat was 1.69 (95% CI, 1.02-2.78); the increments correspond to approximately 2 SDs of intake in the population. Comparing the highest quartile of intake with the lowest, we found an RR of 0.8 (95% CI, 0.5-1.2) for monounsaturated fat and 1.2 (95% CI, 0.9-1.6) for polyunsaturated fat. Saturated fat was not associated with the risk of breast cancer.
CONCLUSIONS:
Our results indicate that various types of fat may have specific opposite effects on the risk of breast cancer that closely resemble the corresponding effects in experimental animals. Research investigations and health policy considerations should take into account the emerging evidence that monounsaturated fat might be protective for risk of breast cancer.

The Lancet, Volume 297, Issue 7697, Pages 464 – 467, 6 March 1971
INCIDENCE OF CANCER IN MEN ON A DIET HIGH IN POLYUNSATURATED FAT
Morton Lee Pearce, Seymour Dayton
In an eight-year controlled clinical trial of a diet high in polyunsaturated vegetable oils and low in saturated fat and cholesterol in preventing complications of atherosclerosis, 846 men were assigned randomly to a conventional diet or to one similar in all respects except for a substitution of vegetable oils for saturated fat. Fatal atherosclerotic events were more common in the control group (70 v.48; P<0·05). However, total mortality was similar in the two groups: 178 controls v. 174 experimentals, demonstrating an excess of non-atherosclerotic deaths in the experimental group. This was accounted for by a greater incidence of fatal carcinomas in the experimental group. 31 of 174 deaths in the experimental group were due to cancer, as opposed to 17 of 178 deaths in the control group (P=0·06).

Isr J Med Sci. 1996 Nov;32(11):1134-43.
Diet and disease–the Israeli paradox: possible dangers of a high omega-6 polyunsaturated fatty acid diet.
Yam D, Eliraz A, Berry EM.
Israel has one of the highest dietary polyunsaturated/saturated fat ratios in the world; the consumption of omega-6 polyunsaturated fatty acids (PUFA) is about 8% higher than in the USA, and 10-12% higher than in most European countries. In fact, Israeli Jews may be regarded as a population-based dietary experiment of the effect of a high omega-6 PUFA diet, a diet that until recently was widely recommended. Despite such national habits, there is paradoxically a high prevalence of cardiovascular diseases, hypertension, non-insulin-dependent diabetes mellitus and obesity-all diseases that are associated with hyperinsulinemia (HI) and insulin resistance (IR), and grouped together as the insulin resistance syndrome or syndrome X. There is also an increased cancer incidence and mortality rate, especially in women, compared with western countries. Studies suggest that high omega-6 linoleic acid consumption might aggravate HI and IR, in addition to being a substrate for lipid peroxidation and free radical formation. Thus, rather than being beneficial, high omega-6 PUFA diets may have some long-term side effects, within the cluster of hyperinsulinemia, atherosclerosis and tumorigenesis.

When cancers are mestatasizing, their phospholipids contain less stearic acid than the less malignant tumors (Bougnoux, et al., 1992), patients with advanced cancer had less stearic acid in their red blood cells (Persad, et al., 1990), and adding stearic acid to their frood delayed the development of cancer in mice (Bennett, 1984). The degree of unsaturation of the body’s fatty acids corresponds to resistance to several types of cancer that have been studies (Hawley and Gordon, 1976; Singh, et al., 1995). -Ray Peat, PhD

Breast Cancer Res Treat. 1992 Mar;20(3):185-94.
Prognostic significance of tumor phosphatidylcholine stearic acid level in breast carcinoma.
Bougnoux P, Chajes V, Lanson M, Hacene K, Body G, Couet C, Le Floch O.
The involvement of lipid enzymes in the action of oncogenes at the cell membrane level has suggested that membrane lipids could play a role in modulating the growth of tumors. We previously found that breast cancer patients with a low level of polyunsaturated fatty acids in their primary tumor’s phosphatidylethanolamine had a high risk of early occurrence of visceral metastasis. In the present study, we prospectively examined whether fatty acid composition of tumor membrane phosphatidylcholine had a prognostic significance in a series of 63 patients with a localized presentation of breast cancer. Membrane phospholipids were extracted from the carcinoma tissue obtained at the time of surgery, phosphatidylcholine was purified, and its fatty acids were analyzed by capillary gas chromatography. During the follow-up period, 20 patients developed metastasis. In these patients, the proportion of stearic acid containing phosphatidylcholine was significantly lower than it was in the tumors of the 43 patients who remained metastasis-free. Multivariate analysis according to Cox showed that low stearic acid level in tumor phosphatidylcholine and high mitotic index were independently predictive of subsequent metastasis. The predictive value of stearic acid level on metastasis risk was higher in node-positive patients than in node-negative patients, allowing individualization of a subgroup of low stearic acid level, node-positive patients with very poor prognosis. We concluded that stearic acid level in tumor membrane phosphatidylcholine is an independent intra-tumor marker of breast cancer prognosis. This finding is new evidence that tumor’s structural lipids are linked to the growth of breast cancer.

Br J Urol. 1990 Mar;65(3):268-70.
Erythrocyte stearic to oleic acid ratio in prostatic carcinoma.
Persad RA, Gillatt DA, Heinemann D, Habib NA, Smith PJ.
The red cell membrane stearic acid to oleic acid ratio was analysed in 34 men with histologically proven carcinoma of the prostate and distant metastases. This ratio was expressed as the saturation index (SI). A mean SI of 0.97 was found in control patients without evidence of any malignancy whereas all patients with advanced prostatic cancer showed a reduced stearic to oleic acid ratio (mean SI 0.466). Untreated patients had a significantly lower SI (mean 0.36) than those who had responded to hormonal therapy (mean 0.547; P less than 0.0001). A drop in SI correlated well with more advanced disease as judged by radiological findings and serum PSA. It is suggested that red cell membrane SI correlates well with radiological and biochemical markers of advanced prostatic carcinoma and may be used as a marker to assess progress and response to treatment.

Int J Cancer. 1984 Oct 15;34(4):529-33.
Effect of dietary stearic acid on the genesis of spontaneous mammary adenocarcinomas in strain A/ST mice.
Bennett AS.
Strain A/ST female mice maintained on a high fat (15%) diet in which stearic acid was the major lipid component developed initial spontaneous mammary adenocarcinomas at an older age than mice fed a low fat (4.5%) stock diet. Mice placed on the SA diet at weaning developed tumors at 15.7 +/- 0.87 months compared to 12.7 +/- 0.43 months for those retained on the stock diet (p less than .05). Placing mice on the SA diet at 11.5 months resulted in a smaller but significant increase in the latency period (5.0 +/- 0.86 vs 3.0 +/- 0.57 months +/- 0.57 mo), (p less than .05). Fatty acid analyses of non-tumorous mammary tissue from mid-pregnant mice and of tumor tissues showed that feeding large amounts of 18:0 did not result in increases in the proportion of 18:0. Significant reductions in the percentages of polyunsaturated fatty acids (PUFA) was found in tissues on mice fed the SA diet. The percentage of 18:2 was reduced in both types of tissues; 20:3 and 20:4 was reduced in tumor tissues. Distribution of C18 fatty acids in plasma membranes of tumors of mice fed the two diets were similar; percentages 18:2 was higher in plasma membranes of non-tumorous tissues of mice fed the SA diet. These results suggest that dietary stearic acid interferes with the availability of certain PUFA required for tumor production.

Lab Invest. 1976 Feb;34(2):216-22.
The effects of long chain free fatty acids on human neutrophil function and structure.
Hawley HP, Gordon GB.
Neutrophils from healthy volunteers were isolated and incubated with varying concentrations of albumin-bound long chain free fatty acids. Standard in vitro function tests including phagocytosis, bactericidal activity, and chemotaxis were performed after the incubation. It was found that unsaturated fatty acid (oleic acid) caused no changes in bactericidal activity and only moderate decreases in phagocytosis and chemotaxis at very high concentrations. Saturated fatty acid (palmitic acid) produced, at high concentrations, virtually complete inhibition of chemotaxis and moderate depression of phagocytosis and bactericidal ability. Most significantly, lower concentrations of saturated free fatty acids, within the range reported clinically in various diseases, caused a marked inhibition of chemotaxis. These functional disturbances were associated with ultrastructural alterations. Neutrophils treated with oleic acid contained numerous cytoplasmic neutral lipid droplets. Neutrophils incubated with palmitic acid showed elongated cleftlike dilations of the endoplasmic reticulum and degenerative degranulated cytoplasmic areas. It is postulated that these represent crystallization of excess saturated free fatty acids or triglyceride which interfere with chemotaxis, either mechanically or by causing cell injury.

Invasion Metastasis. 1995;15(3-4):144-55.
Stearate inhibits human tumor cell invasion.
Singh RK, Hardy RW, Wang MH, Williford J, Gladson CL, McDonald JM, Siegal GP.
Tumor growth and metastasis are affected by changes in membrane lipid composition, however, little is known regarding the role of specific fatty acids in these pathological events. We investigated the effects of the long-chain saturated fatty acids (LCSFA), myristate (C14:0), palmitate (C16:0) and stearate (C18:0) on two key steps of metastasis: cell adhesion and invasion into extracellular matrix (ECM). Using a new 72-hour ECM (Amgel) invasion assay, we demonstrated that the exposure of highly invasive human fibrosarcoma HT-1080 cells to 0.3 mM stearate inhibited their ability to traverse Amgel by 59.4 +/- 8%. In contrast, treatment of tumor cells with 0.3 mM myristate or palmitate had no effect. Microscopic examination revealed a time-dependent inhibition of tumor cell adhesion to the Amgel in the stearate-treated group. Cell adhesion assays further showed a series of rapid morphological cellular changes, i.e. retraction of processes, cell rounding, and subsequent detachment in the presence of stearate. These morphological events were both dose- and time-dependent. Viability of LCSFA-treated cells exceeded 80%. This stearate inhibition of HT-1080 cell adhesion was also observed with two other invasive human tumor cell lines. Similar treatment of HT-1080 cell with the unsaturated long-chain fatty acid oleate (C18:1) did not alter tumor cell adhesiveness. In contrast, nontransformed human fibroblasts (Hs-68) were unaffected by stearate treatment. This inhibition of cell adhesion by stearate was determined to be dependent upon laminin-containing ECM. Pretreatment of HT-1080 cells with stearate dramatically abolished their capacity to attach to laminin but not to collagen type IV or fibronectin matrices. Immunofluorescent studies with anti-beta 1 integrin receptor and antivinculin antibodies demonstrated beta 1 subunit and vinculin colocalization to focal adhesions in untreated HT-1080 cells adherent to laminin, in contrast to stearate-treated tumor cells. Further, stearate-induced changes were shown to be functionally coupled to integrins as an anti-beta 1 antibody markedly diminishes the adhesive ability of tumor cells to laminin. These data demonstrate stearate inhibits tumor cell adhesion, and therefore invasion, via a mechanism involving a laminin integrin receptor.

Nat Commun. 2012 Sep 11;3:1053.
High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring.
de Assis S, Warri A, Cruz MI, Laja O, Tian Y, Zhang B, Wang Y, Huang TH, Hilakivi-Clarke L.
“To test our hypothesis that maternal exposures during pregnancy to factors such as HF diet or a synthetic E2 lead to breast cancer in several generations, we fed pregnant Sprague–Dawley rats (F0) with either an AIN93G control diet or an isocaloric AIN93G-based high fat diet, containing 43% energy from corn oil, throughout gestation.”
“Maternal exposures to environmental factors during pregnancy influence the risk of many chronic adult-onset diseases in the offspring. Here we investigate whether feeding pregnant rats a high-fat (HF)- or ethinyl-oestradiol (EE2)-supplemented diet affects carcinogen-induced mammary cancer risk in daughters, granddaughters and great-granddaughters. We show that mammary tumourigenesis is higher in daughters and granddaughters of HF rat dams and in daughters and great-granddaughters of EE2 rat dams. Outcross experiments suggest that the increase in mammary cancer risk is transmitted to HF granddaughters equally through the female or male germ lines, but it is only transmitted to EE2 granddaughters through the female germ line. The effects of maternal EE2 exposure on offspring’s mammary cancer risk are associated with changes in the DNA methylation machinery and methylation patterns in mammary tissue of all three EE2 generations. We conclude that dietary and oestrogenic exposures in pregnancy increase breast cancer risk in multiple generations of offspring, possibly through epigenetic means.”

Cancer Res. 1987 Mar 1;47(5):1333-8.
Effects of dietary fats and soybean protein on azaserine-induced pancreatic carcinogenesis and plasma cholecystokinin in the rat.
Roebuck BD, Kaplita PV, Edwards BR, Praissman M.
Both dietary unsaturated fat and raw soybean products are known to enhance pancreatic carcinogenesis when fed during the postinitiation phase. A comparison of these two dietary components was made to evaluate the relative potency of each ingredient for enhancing pancreatic carcinogenesis and to determine if this enhancement was correlated with an increase in plasma cholecystokinin (CCK) levels. Male Wistar rats were initiated with a single dose of azaserine (30 mg/kg body weight) at 14 days of age. The rats were weaned to test diets formulated from purified ingredients. Dietary protein at 20% by weight was either casein or soy protein isolate (heat treated or raw). Corn oil was the unsaturated fat of major interest and it was fed at either 5 or 20% by weight. Pancreases were quantitatively evaluated for carcinogen-induced lesions at 2- and 4-month postinitiation. In a second experiment designed to closely mimic the above experiment, rats were implanted with cannulae which allowed plasma to be repetitively sampled over a 2.5-week period during which the test diets were fed. Plasma was collected both prior to introduction of the test diets and afterwards. Plasma CCK was measured by a specific radioimmunoassay. Both the 20% corn oil diet and the raw soy protein isolate diet enhanced pancreatic carcinogenesis. The effects of the raw soy protein isolate on the growth of the carcinogen-induced lesions were significantly greater than the effects of the 20% corn oil diet. Plasma CCK values were not elevated in the rats fed the 20% corn oil diet, but they were significantly elevated in the rats fed the raw soy protein isolate. Heat-treated soy protein isolate neither enhanced carcinogenesis nor elevated the plasma CCK level. This study demonstrates that certain plant proteins enhance the growth of carcinogen-induced pancreatic foci and that this effect is considerably greater than the enhancement by high levels of dietary unsaturated fat. Furthermore, the enhancement by the raw soy protein isolate may be mediated by CCK; but this does not appear to be the mechanism by which the unsaturated fat, corn oil, enhances pancreatic carcinogenesis.

Nutr Cancer. 1987;9(4):219-26.
Melanoma and dietary lipids.
Mackie BS, Mackie LE, Curtin LD, Bourne DJ.
Samples of subcutaneous adipose tissue were taken from 100 melanoma patients and 100 matched controls in Sydney in 1984-1985 and were analyzed for constituent fatty acids. The mean percentage of linoleic acid in the triglycerides of the subcutaneous adipose tissue (PLASAT) of these subjects was substantially higher than that in a similar group examined in 1975-1976. In addition, the percentage of polyunsaturated fatty acids was found to be higher in the melanoma patients than in the controls (p less than 0.01), and there were significantly more controls than patients who had a low PLASAT (p less than 0.01). Relevant literature is quoted and the suggestion is made that increased consumption of dietary polyunsaturates may have a contributory effect in the etiology of melanoma.

International Science and Investigation journal, [S.l.], v. 5, n. 5, p. 157-168, Nov. 2016
Vegetable Oils Consumption as One of the Leading Cause of Cancer and Heart Disease.
NIKNAMIAN, Soroush; KALAMIAN, Miriam.
This review takes a deep look at increases in the incidence of cancer and heart disease after the introduction of industrial vegetable oils in the world. Most vegetable oils are highly processed and refined products, which completely lack the essential nutrients. Omega-6 Linoleic acid from vegetable oils increases oxidative stress in the body of humans, contributing to endothelial dysfunction and heart disease. The consumption of these harmful oils which are high in mega-6 polyunsaturated fats results in changing the structure of cell membrane which contribute to increasing inflammation and the incidence of cancer.

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Tagged with breast, cancer, carcinogensis, linoleic acid, mammory, melanoma, omega 3, omega 6, polyunsaturated fats, PUFA, Ray Peat, saturated fat, seed oils, skin, soy, tumor, unsaturated fats, vegetable oils.

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By Team FPS – November 21, 2011

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