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  1. Artificial Macronutrients , Natural Micronutrients and Disease
    Timothy Bilash MD, MS, OBGYN

    Course Outline and References
    Northern Inyo Hospital Symposium
    Bishop, CA 8/25/2008

    1. Abstract
      1. Commonly, Nutritional Guidelines have focused on Genetic, Hypertensive and Dietary
        Cholesterol Factors in Human Disease, particulary for Heart Attack, Stroke, and Obesity.
        This talk highlights how Artificial Dietary Substances (which dominate in our diet), and
        Nutrient Deficiencies (such as Vitamin B12), have severe health consequences.

    2. Topics
      1. Fructose and Obesity
      2. Trans Fat, Corn Oil , Heart Disease, Cancer
      3. Essential Fatty Acids
      4. Vitamin B12, the Giant Vitamin
      5. The FLING Diet ®

    3. Clinical Objectives
      1. Identify how Fructose and Hydrogenated Fats contribute to Disease
      2. Contrast the Metabolic Effects of Omega-3 and Omega-6 Essential Fatty Acids
      3. Identify 3 Metabolic Pathways for Vitamin B12

  2. Fructose and Obesity

    1. High Fructose Corn Syrup

      1. Sucrose (Table Sugar) is made up of
        one Glucose + one Fructose , bonded together [182]


      2. Sucrose is digested in the Intestines by the enzyme Sucrase ,
        producing Free Glucose + Free Fructose [183]


      3. High Fructose Corn Syrup is manufactured from Corn Starch . [181]

      4. High Fructose Corn Syrup from Corn Starch results in a mixture of
        Free D-Glucose and Free D-Fructose, as unbound Monsaccharides . [183]



        1. Free D-Glucose (and D-Fructose) equilibrates in solution to a mixture of Alpha and
          Beta forms, which for Glucose is in the ratio of (36%Alpha) to (64%Beta). [188]

        2. There may be more Beta-Glucose when the Free Glucose and Free Fructose in HFCS
          has a chance to equilibrate (36%Alpha/64%Beta) than when Sucrose (Cane/Beet Sugar)
          is enzymatically split and then immediately absorbed at the brush border
          in the Duodenum and Small Intestine (50%Alpha/50%Beta).

        3. High Fructose Syrup Corn Syrup would thus undergo a longer equilibration to Beta
          forms. Alpha-Glucose more readily enters the Glycolitic (Energy), and Beta-Glucose
          more readily enters the Pentose (Anabolic), pathways in Adipose. [189] More of the
          Glucose would be available for Energy as opposed to Storage in this Hypothesis.


      5. Sugar Intake has increased in the United States .

        While there is a decrease in Sucrose consumption, HFCS and total Sugar
        consumption has skyrocketed. [185]



      6. Obesity Increase parallels Increases in HFCS and Free Fructose
        in the United States. [Bray 186]

        1.  



      7. Fructose stimulates its Intestine Transporter Protein GLUT5. [184]
        Fructose Metabolism gives some clues that a mechanism of Obesity
        is related to Sugar Absorption.
        High Fructose ( GLUT5 Transport) increases the concentration of
        its own Glut5 Transporter Protein by 50%.
        Glucose ( GLUT1 Transport), in contrast, has no effect on
        its own GLUT1 Transporter Protein.


         


      8. Fructose increases Its Own Uptake from the Intestine .

        This is likely related to the GLUT5 concentration increase above. (There is
        another complicated mechanism of Fructose co-transport with Glucose
        which is not discussed here). [184]

         


    2. Metabolism of Sugar ( MonoSaccharides ) [42-48,44a]

      1. Overview of Glucose/Fructose Absorption and Transport

        1. First , Sugars are ABSORBED from the Intestine lumen
          and TRANSPORTED to the Liver in steps:

          1- From the Intestinal Lumen (GLUT2)
          2- Into Enterocyte across the epithelium on the lumen side ( SGLUT1 vs GLUT5 )
          3- Out from the Enterocyte on the non-lumen side into the Portal Vein Blood ( GLUT2 )
          3- Into the Liver cell ( GLUT2 ) from the Portal Vein
          4- Inside the Liver cell , Sugars need to be trapped ( phosphorylated ) and
          then metabolized
          5 - Sugars follow a concentration gradient

        2. Glucose Transport Proteins (GLUT) are needed to transport Sugar in or out of cells
          1. These "Small" 6 carbon Hexose sugars (Glucose, Fructose) are
            too large to cross cell membrane without "carriers" . [48a]  




        3. Absorption into the Intestine Cell (from the Gut)
          Glucose/ SGLUT1 vs Fructose/ GLUT5

          1. Glucose ( from the Gut)
            1. GLUCOSE is absorbed from the Gut into the Enterocyte thru
              Active Diffusion [SGLUT 1 ] .
            2. Glucose absorption from the intestine is thus energy dependent
              and rate limited , a facilitated transport .
            3. SGLUT1 is the transporter that carries Glucose into the Enterocyte .
              It is a sodium-dependent hexose transporter which transports
              both glucose and sodium ion into the cell, and in fact
              will not transport either alone.
            4. Once inside the enterocyte , Glucose and Sodium must then be
              co-exported from the cell into blood to allow further absorption.
              Sodium is exchanged for potassium by the sodium pumps,
              which maintains the electrochemical gradient across the epithelium.
              The energy stored in this gradient is actually what is driving Glucose entry.

          2. Fructose ( from the Gut)
            1. FRUCTOSE is absorbed from the Gut into the Enterocyte thru
              Passive Diffusion [GLUT 5 ] .
            2. Fructose absorption from the Intestine is thus energy in-dependent
              and diffusion limited .
            3. GLUT5 another hexose transporter, transports Fructose into
              the Enterocyte
            4. Fructose is not co-transported with sodium.

        4. Transport into the Portal Blood
          1. GLUT2 transports both Glucose and Fructose out of the Enterocyte
            into the Portal Blood. They diffuse "down" a concentration gradient into
            capillary blood and enter the Portal System .

        5. Entry into/out of the Liver
          1. GLUT2 transports both Fructose and Glucose into and out of the Liver
            down a concentration gradient.


      2. Second , SUGAR is digested in the Liver, to Glycogen or Fat , or
        converted to Energy.

        1. Glycolysis in the Liver: Fructose vs Glucose Hexose Pathways [42]



        2. Glucose Digestion in the Liver

          1. Glucose breakdown to (GAP+ DAP) is metabolically rate limited . [42]

          2. INITIATION : Glucose metabolism to G-6-P (used to make Fat,
            Glycogen, or Energy) is metabolically controlled
            thru Hexokinase [ HK ] & Glucokinase [ GK ] .
            1. Hexokinase is dominant at low sugar concentrations
              (product-inhibited)
            2. Glucokinase is active at high sugar concentrations
              (turned on with more Glucose, not product-inhibited)

          3. CONTROL : Subsequent breakdown to GAP+ DAP is metabolically controlled
            thru PhosphoFructokinase [ PFK -1 and PFK -2 ]
            1. PhosphoFructokinase -1 [ PFK -1] produces Fructose1,6P
              1. High levels of ATP , Citrate , and Low pH (Lactic Acidosis ) inhibit PFK -1
              2. Ammonia activates PFK -1
            2. PhosphoFructokinase -2 [ PFK -2 ] produces Fructose2,6P
              1. PFK -2 is controlled by the hormones Insulin and Glucagon .
              2. Fructose2,6P is a potent activator of PFK -1

        3. Fructose Digestion in the Liver

          1. Fructose, however, by-passes rate control steps
            for breakdown to GAP+ DAP . [42]

          2. INITIATION : Fructose metabolism to F-1-P is not metabolically controlled
            thru Fructokinase [ HK ]
            1. Fructose intitiation to F1P has no product inhibition
              ( immediate conversion , used to make Fat, Glycogen, or Energy)
            2. Fructokinase has no product inhibition. The higher the
              Fructose level, the more enters the Liver and is stored
            3. Excess Fructose is thus easily stored as Fat.
              Fructose (or high Sucrose=Fructose+Glucose) rapidly
              enters the Glycolysis pathway, leading to Fat Synthesis

          3. CONTROL : F-1-P breakdown to GAP+ DAP is not metabolically controlled


      3. Feeding Effects on Liver Glycolysis

        1. Fructose also acts as a trigger for Sugar metabolism

          1. Glucokinase normally produces Glycogen and Pyruvate
            only at higher Blood Glucose .
          2. Trace levels of Fructose, however, activates Glucokinase ***
            1. Fructose increases Glucokinase actvity and Glucose storage ,
              by inducing transport of Glucokinase back into the Cytosol
              from the Nucleus.
            2. Fructose also dissociates the Glucokinase /Receptor complex,
              which further activates Glucokinase .
            3. These activations occurs within 10 minutes, at Fructose concentrations
              above 5mM, with maximum activity above 25mM. Glucose also does this,
              but only at higher concentrations.
          3. R estricting carbohydrates decreases calories burned by
            lowering basal metabolism, limiting weight loss.
          4. Restriction of protein and fat maintains basal metabolism, allowing
            greater weight loss. [44a]

        2. Normal Metabolism of Glucose and Fructose in the Liver after a meal:
          Glycogen, Fatty Acids, and ATP are produced [42]



        3. Fructose markedly catalyses Glucokinase , increasing Glycogen and
          Fatty Acid Flux in the Liver. High Sugar flux produces Fat to be stored.




      4. Third , SUGAR is RELEASED from the Liver into the Arterial Blood

        1. Only Liver and Kidneys can mobilize Glucose
        2. Glucose-6- Phosphatase releases Glucose , balanced by Glucokinase
          which stores Glucose .
          1. Glucokinase adds a Phosphate to Sugar, initiating storage.
          2. Glucose-6- Phosphatase cleaves that Phosphate, releasing
            Glucose to transport across the membrane.
          3. Liver and Kidney can also synthesize Glucose from Amino Acids
            (derived from Proteins in the Diet, or from the body's Muscle Mass)


      5. Fourth , SUGAR is OXIDIZED in the Cells

        1. Liver is the only organ that can process Fructose , because it contains Fructokinase
        2. Muscle and Brain cannot burn Fructose .
          1. Muscle burns Glucose or Fat
            1. Fructose provides muscle energy only after the
              Liver has converted it to Glucose or Fat
            2. Fructose is also converted to Glucose by Muscle Hexokinase , but this is
              inhibited at high Fructose concentrations
            3. Muscle activity increases Glucose entry into Muscles (exercise lowers Blood Sugar).
          2. Brain can only burn Glucose
            1. Fructose provides energy only after the Liver has converted it to Glucose
            2. Fatty Acids have no uptake mechanism in the Brain so cannot supply brain energy.
            3. Ketone Bodies (Acetyl Acetate or ß-Hydroxybutyrate ) can diffuse into the brain,
              but it takes almost two weeks to adapt to starvation . At most, Ketone Bodies
              provide about 50% of the brain's energy, the balance must still come from Glucose.

      6. Warming Fructose in food processing converts its 5-ring form to a 6-ring. The metabolic
        effects of this is unclear.


    3. Fructose makes you hungry (Elliott 2002) [44]
      Sugar and Fructose consumption has gone UP!



    4. Fructose Summary

      1. High Fructose Corn Syrup ( HFCS ) contains 42%- 55% Fructose.
        It is produced thru high temperature hydrolysis of Corn Starch . The
        resulting Glucose Syrup is then enzymatically isomerized to the sweeter
        High Fructose + Glucose Syrup ( HFCS ) and used in foods.
      2. Fructose does not stimulate Insulin Release (no GLUT5 in ß cells) ,
        so Fructose consumption does not dampen appetite .
      3. " Fructose has been implicated as a contributor to nearly all of the classic
        manifestations of the Insulin Resistance Syndrome ." [44]
      4. Fructose feeds sugar continuously into Fat production .
      5. Fructose when eaten just before 2 hours of exercise is oxidized (burned)
        less than is Glucose or Resistant Starch (54% vs 70%). [46]
      6. " It is preferable to consume dietary Carbohydrates in the
        form of Glucose " (Glucose and Resistant Starch) rather than Fructose ,
        based on the endocrine and metabolic effects. [44a]


    5. Resistant Starch [45]
      1. Resistant starch ( RS ) is any starch that is not digested in the small intestine and
        passes to the large bowel for fermentation.
      2. Calories from RS that are undigested in the small intestine can be salvaged by fermentation
        to short-chain fatty acids ( SCFA ; acetate, butyrate, proprionate ) by the microflora of the large bowel.
      3. Retrograded Amylose (a linear polymer of glucose residues linked by Alpha Bonds ),
        such as cooked and cooled starchy foods like pasta salad , and
        native starch granules, such as found in high-amylose maize starch and bananas ,
        are the major components of dietary Resistant Starch.
      4. High Fructose Corn syrup contains Beta Bonds .
      5. Replacement of 5.4% of total dietary carbohydrate with RS significantly increased
        post-prandial lipid oxidation and therefore could decrease fat accumulation in the long-term.
        More Fat was oxidized at the 5.4% RS relative to the 0% RS meal, with a concomitant decrease in
        total carbohydrate oxidation. A hypothesis is that higher dietary RS (10.7%) also acts like dietary fiber. [46]


  3. Fatty Acids

    1. Chain Length of Fatty Acids [157]

      1. Fatty Acids with 4 to 12 carbon atoms are found mainly in Milk Fats
        (mainly Butyric in Cow and Decanoic in sheep), Coconut and Palm Oils.

        1. Short-chain fatty acids have four to six carbon atoms.
          1. These fats are always saturated.
          2. Four-carbon butyric acid is found mostly in butterfat from cows, and six-carbon
            capric acid is found mostly in butterfat from goats.
          3. They do not need to be acted on by the bile salts and are directly absorbed
            for quick energy. For this reason, they are less likely to cause weight gain than
            olive oil or commercial vegetable oils
          4. These fatty acids have antimicrobial properties—that is, they protect us from
            viruses, yeasts and pathogenic bacteria in the gut.
          5. Short-chain fatty acids also contribute to the health of the
            immune system.
        2. Medium-chain fatty acids have eight to twelve carbon atoms and are found
          mostly in butterfat and the tropical oils.
          1. Like the short-chain fatty acids,
            these fats have antimicrobial properties; are absorbed directly for quick
            energy; and contribute to the health of the immune system.
        3. Long-chain fatty acids have from 14 to 18 carbon atoms and can be either
          saturated, monounsaturated or polyunsaturated. [157]
          1. Stearic acid is an 18-carbon saturated fatty acid found chiefly in beef and
            mutton tallows.
          2. Oleic acid is an 18-carbon monounsaturated fat which is the chief
            component of olive oil.
          3. Another monounsaturated fatty acid is the 16-carbon palmitoleic acid which
            has strong antimicrobial properties. It is found almost exclusively in animal
            fats.
          4. The two essential fatty acids LNA and LA are also long chain, each
            18 carbons in length.
          5. Another important long-chain fatty acid is gamma-linolenic acid
            ( GLA ) which has 18 carbons and three double bonds. It is found in evening
            primrose, borage and black currant oils. Your body makes GLA out of
            omega-6 linoleic acid and uses it in the production of substances called
            prostaglandins , localized tissue hormones that regulate many processes at
            the cellular level.
          6. Stearic acid is reported to be neutral in terms of blood cholesterol concentration.
            The stearic acid content of milk fat is 12.1g/100g. Therefore, if stearic acid were
            redefined from a saturated fat, then the saturated fat content of milk fat drops from
            51.3g to 39.2g/10 g. [29]
        4. Very-long-chain fatty acids have 20 to 24 carbon atoms.
          1. They tend to be highly unsaturated, with four, five or six double bonds.
          2. Some people can
            make these fatty acids from EFA's , but others, particularly those whose
            ancestors ate a lot of fish, lack enzymes to produce them. These "obligate
            carnivores" must obtain them from animal foods such as organ meats, egg
            yolks, butter and fish oils.
          3. The most important very-long-chain fatty acids are dihomo-gamma-linolenic
            acid ( DGLA ) with 20 carbons and three double bonds; arachidonic acid (AA)
            with 20 carbons and four double bonds; eicosapentaenoic acid (EPA) with
            20 carbons and five double bonds; and docosahexaenoic acid ( DHA ) with
            22 carbons and six double bonds.
          4. All of these except DHA are used in the production of prostaglandins ,
            localized tissue hormones that direct many processes in the cells.
          5. In addition, AA and
            DHA play important roles in the function of the nervous system.
        5. Note that some report Fat Ratios by weight, others by molar ratios. As well, the
          classification of chain length is slightly different for Essential Fatty Acids.


    2. (De)Hydrogenation of Fats [25-36]

      1. Three Classes of Fatty Acids

        a: Saturated(soft fat) , b: Cis-Unsaturated (oil) , c: Trans-Unsaturated(hard fat)

        1. ( " Saturated " ) / Fully-Hydrogenated Fatty Acids
          1. No double bonds (only single bonds) CH 3 -(CH 2 ) n -COOH
            in a chain of (n+1) carbons:

            1. Animal Fat
            2. Soft at room temperature, flexible (medium temperature)
            3. No Dehydrogenation is Full Hydrogenation (no removal of hydrogens)
            4. Increased Health risks, Increased LDL levels
          2. Ex: Stearic Acid (a major component of Animal Fat)
            All 18 Carbon atoms single bond in a floppy chain (no double bonds) [34,35]


        2. (" Cis-Unsaturated ") / Cis-Partial (De)Hydrogenated Fatty Acids

          1. One or more Cis double bonds in a chain of otherwise single bonded carbons:


            1. Seed Oils, Naturally-occurring
            2. Liquid at room temperature ( Cis low temperature )
            3. Partial Hyd rogenation is Partial Dehyd rogenation
            4. Improved Health
          2. Ex: Oleic Acid, Monounsaturated ( Cis w-9, a major component of Olive Oil)
            18 Carbon Atoms, most single bonds in a chain (one double bond in a Cis kink ) [34,35]


        3. ( " Trans-Unsaturated " ) / Trans-Partial (De)Hydrogenated Fatty Acids

          1. One or more Trans double bonds in a chain of otherwise single bonded carbons:

            1. Artificially produced, Industrial Waste Product
            2. Solid at room temperature, inflexible ( Trans high temperature )
            3. "Partially Hydrogenated Vegetable Oil", "Vegetable Shortening"
            4. Partial Hydrogenation is Partial Dehydrogenation
            5. Partial Hydrogenation destroys some Essential Fatty Acids
              (such as Linolenic and Linoleic acid) which oxidize to become rancid.
              This extends shelf life but removes nutrient value.
          2. Ex: Elaidic Acid Monounsaturated (Trans w-9, a major component
            of Vegetable Oil)
            18 Carbon atoms in a straight , rigid configuration [34,35]



      2. Fatty Acid Structural Differences (3 Types of Carbon Double Bonds)

        Trans -Unsaturated( Hard Fat ) / Saturated ( Soft Fat ) / Cis -Unsaturated ( Oil ) [33]



      3. Fatty Acids are Components of Membranes

        1. Fatty acids are the "two-by-fours" which build membranes
        2. Membrane Phospholipids [40a]



        3. Membrane Structure[40b]



        4. Saturated (Soft) vs Cis-Unsaturated (Oil) Fatty Acid Properties

          The type of Fatty Acid changes the Fluidity properties:

          Cis -Unsaturated (Bent, Poorly Packed) = Oil
          Saturated (Straight, Floppy) = Soft Fat
          Trans -Unsaturated (Straight, Stiff, Well Packed) = Hard Fat


        5. Saturated and Essential Fatty Acids in Animal and Plant Fats and Oils [181]
          (Note that vegetable oils tend to have higher Linoleic Acid - w6 content)




      4. Health Effects of POLYUNSATURATED( PUFA ) & TRANS( TFA ) FATS

        1. Hydrogenation of Fat [29e,32,32b]

          1. Partial hydrogenation , the process used to create Trans Fatty Acids , is
            primarily used to produce solid fats . However, it also removes essential
            polyunsaturated fatty acids , such as linolenic acid (omega 3) and
            linoleic acid (omega 6), which although tend to oxidize and cause the fat to become
            rancid with prolonged storage or when exposed to the high temperatures
            used for commercial deep-fat frying.
            Natural (Low-temperature) Trans fatty acids are also produced
            in the rumen of cattle, resulting in low levels of these isomers in dairy
            and beef fat. These have different properties from the Artificial Trans Fats. [29e]
          2. Production of partially hydrogenated fats began early in the 20th
            century and increased steadily until about the 1960s, as processed
            vegetable fats displaced animal fats in the diets of most people in
            industrialized countries. [29e]
          3. Vegetable Fat consumption has increased , particularly Trans Fat ;
            1. Trans Fat represents 2.6% of average American's total caloric intake.
            2. Saturated Fat represent 12.5% of total calories.
          4. Animal Fat has stayed constant or slightly declined , while Cancer Incidence
            and Mortality have increased . Trans fat consumption was always a significant
            factor in the multiple correlation analysis for total cancer deaths ( Enig and
            Munn 1978). [100,132]
          5. New Food Labeling of Trans Fats
            1. Trans Fat of less than 0.5gm/serving can be labeled 0gm Trans Fat

        2. Fat Source Effect on LDL , HDL [39]

          1. Note that Essential Monunsaturated and Polyunsaturated Fats contain CIS
            and no Trans double bonds. Saturated Fats have no double bonds at all.

        3. LDL / HDL Ratios [ Ascherio 29a, Almendingen 29g]


          1. Studies replace (10% of Total Energy) or (Soy + 70%) of the indicated Fatty Acid
          2. Poly-Unsaturates (Trans-Hydrogenation) double the LDL / HDL Ratio.
          3. Margarines are usually higher in Cis-Polyunsaturated Fat than Butter.
            A reduction in LDL / HDL is obtained with Low-Trans Tub Margarine (Soft)
          4. Note that when Soy Oil in Diet is high, there is little difference in the LDL / HDL ratio
            between adding Butter or Poly-Unsaturated Oils. Replacement of Butter with
            Hard stick Margarine (20-25% Trans Fat) has the same effect on the HDL Cholesterol Ratios.
          5. HDL and LDL are not the only risk factors for Cardiovascular Disease. Other
            factors (effects on inflammatory Prostaglandins ) alter these risks, probably
            to a greater degree.

        4. Triglyceride Levels

          1. Hydrogenated Corn Oil feeding results in higher Triglyceride levels
            than with Natural Oils or Butter
          2. Saturated Fatty Acid has little effect on Triglyceride levels
            if substituted for Cis-Unsaturated

        5. Trans Fat Effect on Coronary Disease

          1. "Artificial" (Hydrogenated) Trans Fat
            1. LDL / HDL Ratio for Trans Fat is twice that for Saturated Fat
              1. Trans Fat increases LDL and decreases HDL
              2. Saturated Fat raises LDL only (and depending on chain length,
                some lower or do not affect LDL )
            2. Severe Coronary Risk: 30,000 premature Coronary Heart Deaths
              attributable to Artifical Trans Fat
            3. Per capita consumption has not changed greatly since the 1960’s
              because of the increased use in commercially-baked and fast foods
          2. " Natural" Trans Fat are found in Dairy and Beef (5%). These have
            different properties from the artifically produced ones.

        6. Trans Fat Effect on Long Chain Essential Fats (EPA, DHA )
          1. Trans Fats inhibit the conversion of AlphaLinoleic Acid ( LNA )
            to longer-chain Omega-3's Eicosapentanoic Acid (EPA) and
            Docosahexaenoic ( DHA )
          2. This reduces the availability of DHA and EPA in Arterial cells, potentially
            enhancing the development of Coronary Heart Disease .
          3. Trans Fats appear to interfere with Fetal Growth and Length
            of Gestation , indicated by an inverse correlation between the TFA
            and DHA levels in the circulation of Infants (Elias and Innis 2001). [38b]

        7. PUFA ( Cis Double Bonds): Coronary Disease

          1. Polyunsatruated Fat: increases Atherosclerosis [29j,96]
            1. Although Polyunsaturated Fats are protective against Cardiac
              Arrhythmias ( LNA or its metabolites appear to decrease Cardiac
              Arrhytmias ), a study of post-menopausal women with a relatively
              low fat intake showed that Polyunsaturated Fat was positively
              associated with progression of Coronary Atherosclerosis .
              Monounsaturated Fat ( MUFA ) was not .
            2. This probably is an indication of the greater vulnerability of
              Polyunsaturated Fats to Lipid Peroxidation . The greater the degree
              of unsaturation in a fatty acid ( ie , the more double bonds in the fatty acid),
              the more vulnerable it is to lipid peroxidation (rancidity). Antioxidants can
              protect unsaturated fat from lipid peroxidation .
            3. The greater the degree of Unsaturation (more double bonds) in a Fatty Acid,
              the more vulnerable it is to lipid peroxidation ( rancidity ).
            4. Antioxidants can protect unsaturated fat from lipid peroxidation .
              Vitamin E has been shown to be protective against this.

          2. Atherosclerosis Mechanism [132]
            1. Plaque Initiation
            2. Plaque Progression
              1. Monocyte adherence
              2. Monocyte invasion
              3. Monocyte transformation to Macrophages
              4. Accumulation of Lipid Products to Macrophage Mebrane Receptors
                and Internalization of Oxidized Low-Density Lipoproteins ( LDL ).
            3. Plaque Rupture


    3. Essential Fatty Acids ( Cis-Unsaturated Double Bonds ) [37,38-38c,41a]

      Essential Fatty Acids ( EFA ) are Cis-Unsaturated Fatty Acids. When ingested,
      they can be converted to longer chain Unsaturated Fatty Acids required in Humans
      (Omega-6 and Omega-3) .

      1. Omega-6 & Omega-3 Essential Fatty Acid Families (82 Harris)


      2. Essential Fatty Acids further convert to important Eicosanoid Products [27]


      3. Omega-3 Fatty Acids [37]



        1. The Omega-3 FA Series begins with Linolenic Acid ( LNA /ALA 18 carbons ).


        2. Linolenic Acid is ultimately metabolized to DHA (22 carbons) [163a]



        3. Linolenic Acid can refer to two completely different substances:
          1. Alpha-Linolenic Acid ( LNA or ALA) is an Omega-3 fatty acid found in some vegetable oils.
            Linoleic Acid usually refers to this forn .
          2. Gamma-Linolenic Acid ( GLA ) is an Omega-6 fatty acid in the Lineleic Acid series

        4. Omega-3 Fatty Acids are AntiInflammatory , AntiThrombotic ,
          AntiArrhythmic , HypoLipidemic , and Vasodilatory .
          1. LNA deficiency causes scaly skin , hair loss , and slow wound healing
          2. There is evidence that Omega-3 is essential for Brain and Retina development [75]

        5. Sources of Linolenic Acid ( LNA )

          1. LNA comes from Greens, and Animals that eat greens (Flaxseed, Fish Oil, Canola, Soy, Walnut,
            Grass-fed Cow Milk/Meat) [92b,92h]
          2. LNA is found in in large quantities in Flaxseed Oil (55%) and in Canola Oil (10%) and
            Un-hydrogenated Soybean Oil (7%).
          3. Estimate LNA =1g/day needed
          4. Most LNA is consumed in Energy production via Beta-Oxidation . [38a]

        6. EPA/ DHA

          1. LNA converts to EPA , further forming 3-series TX's&PG's , decreasing Inflammation
            1. A very small fraction of ingested LNA is converted into Eicosapentanoic Acid
              ( EPA /20 carbons), with a smaller fraction further converting to Docsahexanoic Acid
              ( DHA /22 carbons)
          2. Some LNA is converted to EPA and DHA in Humans
          3. Hi LA (Corn, Safflower OIL) lowers the conversion of LNA to EPA& DHA by using up the del6desaturase.
            1. Del6desaturase is inhibited by Artificial Trans Fats (Hydrogenated Oils), Insulin, and increased Age .
            2. Del6desaturase has a higher affinity for LNA than LA, however.
          4. Better to shift from Hi-w6 to Lo-w6 Oils (Olive, Coconut, Avocado Oils, Grass-fed Organic Butter).


      4. Omega-6 Fatty Acids [41a]

        1. The Omega-6 FA Series begins with Linoleic Acid ( LA/20 carbons ).


        2. Omega-6 Linoleic Acid metabolizes to Arachidonic Acid (AA, 20:4n-6),
          which accumulates to very high concentrations in a wide variety of human tissues and cells.
          1. Arachidonic Acid (AA)


        3. Metabolism of Linoleic Acid (LA) to Aracidonic Acid(AA):
          Enzymes alter the Essential Fat structures step-wise, desaturating and
          elongating, to produce required Fatty Acids. [41]


        4. Omega-6 (w-6) Fatty Acids are ProThrombotic and ProAggregatory ,
          with increases in Blood Viscosity , Vasospasm , and Vasoconstriction . .
          1. While small levels of AA in the body do have some important functions,
            such as in reproduction and other processes, excessively high levels of AA
            are considered to be potentially problematic in the development and/or
            progression of some chronic health conditions.

        5. LA is the precursor to AA [see: Omega Pathways - More Details]
          1. Dietary LA is considered the primary source of AA
          2. LA maintains membrane flexibility
          3. LA increases Vitamin E requirement
          4. Soy diet (high in LA) reduces conversion of LA to AA [131]
          5. AA converts to TX&PG's-series2/ Cycloxygenase & LT-series4/ Lipoxygenase ,
            which promote inflammation , blood clotting , and smooth muscle contractions
            1. High LA inhibits conversion of AA to Inflammatory PG series
            2. High PGE2(inflammatory) induces a switch from the 15- Lipoxygenase
              product of AA, LeukotrieneB4 , to LeukotrieneA4 and Lipoxin A4.
              This counters inflammation and stops polymorphonuclear infiltration,
              resulting in the resolution of the inflammatory process in skin. [132]

        6. LA: Breast Cancer [41a]

          A high consumption of omega-6 polyunsaturated fatty acids ( PUFAs ),
          which are found in most types of vegetable oil, may increase the likelihood
          that postmenopausal women will develop Breast Cancer. Similar effect
          was observed on Prostate Cancer.

        7. Sources of Linoleic Acid (LA)

          1. The primary dietary Omega-6 FA is Linoleic Acid ( LA/18 carbons ). It is found in abundance
            in liquid vegetable oils, with Safflower containing about 75% by weight and Corn Oil about 50%.
            A small portion of LA is converted to AA, a precurser to an array of Eicosanoids (20 carbon metabolites).
          2. Other Oils and Foods that contain Linoleic Acid include Poppy seed Oil (70%), Walnut Oil,
            Palm Oil, Sunflower Oil (63%), Soybean Oil (50%), Peanut Oil (29%), Canola Oil (25%),
            Egg Yolks (16%), Olive Oil (3-21%), Lard (10%), Grass-fed Cow Milk(3%),
            Coconut Oil (2%), Okra, Rice Bran Oil, Wheat germ Oil, Grape seed Oil, Macadamia Oil,
            Pistachio Oil, Sesame Oil. [120]
          3. It is estimated that 2-6 g/day LA needed (Commonly diet has 10-20g). However, University of
            Toronto scientist, Stephen Cunnane discovered that the seminal research used to determine the
            dietary requirement for linoleic acid was based on feeding animals linoleic acid-deficient diets,
            which were simultaneously deficient in n -3 fats. The n -3 deficiency was not taken into account .
            The n -6 oils added back systematically to correct the deficiency also contained trace amounts of n -3 fats.
            Therefore the researchers were inadvertently correcting the n -3 deficiency as well. Ultimately,
            it took more oil to correct both deficiencies. According to Cunnane , this error overestimates
            LA requirements by 5 to 15 times . [120,41a]


      5. Food sources of Essential Unsaturated Fatty Acids

        Vegetables contain c18 Fatty acids, while Marine sources have mostly longer c20
        and c22 Fatty Acids. [92a,121]




    4. OMEGA PATHWAYS: More Detail

      Omega3 Metabolism : LNA (18:3)>EPA(20:5)> DHA (22:6)
      Omega6 Metabolism : LA(18:2)> GLA (18.3)> DGLA (20:3)>AA(20:4)


      1. In a healthy body, a portion of the alpha-linolenic acid ( LNA ) consumed is converted into two forms
        that your body can more readily utilize, DHA and EPA . Unfortunately, this process, which is governed
        by a particular enzyme ( delta-6 desaturase ), is significantly inhibited (up to 50% or more) by an
        overabundance of Linoleic acid. The enzyme is literally “used up” in the desaturation process
        involved in getting rid of excess omega-6 fats, as found in Sunflower Oil and Corn Oil, etc.
        The enzyme is no longer available for converting LNA to it's more usable cousins, DHA and EPA.
      2. In addition, the delta-6 enzyme is also inhibited by the Trans Fatty Acids found in Hydrogenated Oils,
        Margarine, Shortening, and Refined Oils – all significant components of the modern diet. Delta-6 is further
        inhibited by high levels of Insulin , a problem in large percentages of civilized societies where obesity
        and diabetes are soaring. In America, two-thirds of the population is now considered overweight.
      3. Finally, the process of delta 6- desaturation of Linoleic and Alpha-Linolenic Acids slows with aging . [92a]


    5. Long Chain Omega3s ( DHA ,EPA) Suppress Inflammatory Prostaglandins
      from the Omega6/AA Pathway (adapted from [38])


      1. PG's have different effects depending on the Tissue . [77]
        PGF2a , for example decreases Progesterone, which triggers labor in pregnant women.

      2. Anti-inflammatory processes must always continuously counter
        the normal inflammatory processes.
      3. Although most Americans obtain an excess of Linoleic Acid , often it is
        not converted to GLA because of metabolic problems caused by diets
        rich in Sugar, Alcohol or Trans Fats from processed foods, as well as smoking,
        pollution, stress, aging viral infections, and other illnesses such as diabetes. [80]
      4. EPA and DHA (w3 EFA ) reduce Inflammatory Prostaglandins .


    6. Health Effects of Essential Fatty Acids [37,38]

      1. Beneficial Health Effects of w-3 Fatty Acids1

        1. Secondary Prevention of:
          1. Coronary Heart Disease
          2. Hypertension
          3. Type 2 Diabetes
        2. Some Benefit in:
          1. Renal Disease
          2. Rheumatoid Arthritis
          3. Ulcerative Colitis
          4. Crohn disease
          5. Chronic Obstructive Pulmonary Disease

      2. Beneficial Health Effects of w-3 Fatty Acids2

        1. Membrane Fluidity/Omega-3 [96]

          1. Cell membranes of mammals have a higher composition of Long Chain
            Polyunsaturated Fat ( DHA , w-3 fatty acid) and a lower composition of
            Monounsaturated Fat than reptiles. Higher Polyunsaturated membrane
            content gives greater membrane fluidity (and functionality),
            commensurate with the higher metabolic rate of the warm-blooded species.
          2. In Fish , however, increasingly cold environments lead to increasingly high
            cell membrane content of both Monounsaturated and Polyunsaturated
            fatty acids, presumably to maintain greater membrane fluidity
            (and functionality) at the lower temperatures.
          3. Alpha-phosphatidylcholine ( omega-3 double bonds at delta 9, 12, and 15) and
            Gamma-phosphatidylcholin e ( omega-6 double bonds at delta 6, 9, and 12)
            differ only in the location of the unsaturations in one fatty acid chain.
            1. The gel to liquid crystalline phase transition for Omega-3 /Alpha-PC
              membranes exhibits broad hysteresis near -9 degC on heating, and
              -20 degC on cooling.
            2. In contrast, Omega-6 /Gamma-PC membranes does not exhibit hysteresis ,
              and occurs near a lower temperature of -27 degC .
            3. A different molecular ordering exists in the liquid crystalline state.

      3. Beneficial Health Effects of w-3 Fatty Acids3

        1. Thermogenesis /Omega-3
          1. Studies suggest that Omega-3 fatty acids enhance Thermogenesis
            (the burning of excess fat to produce heat), thru "uncoupling protein-3"
        2. Energy Storage/Omega-3
          1. EFA 's shunt glucose (from Carbohydrates) towards glycogen storage/synthesis ,
            at the same time directing Fatty Acids away from Fat storage/ Triglyceride synthesis,
            towards Fatty Acid Oxidation

      4. Beneficial Health Effects of w-3 Fatty Acids4

        1. Prostaglandins (PG) :

          w3 and w6 EFA produce Prostaglandins & Leukotrienes
          thru Cycloxygenase & Lipoxygenase .[75-78]
          1. Cycloxygenase (COX1&2)/PG
            1. COX1
              1. produces baseline prostaglandins
              2. COX1>PGE1 inhibited by ASA, Indometh
              3. Low dose ASA inhibits TXA2(COX1) from Platelets
              4. Low dose ASA does not inhibit PGE2(COX2) from WBC
          2. COX2
            1. produces prostaglandins through stimulation in inflammatory stimulations
            2. NSAID's causes erosive gastritis and renal toxicity by blocking
              PGE2(COX2) in gastric mucosa
          3. Both COX1&2
            1. both found in Blood Vessels, Stomach, and Kidneys
            2. produce TXA2 in the live r. TXA2 releases TNFa , and both
              cause Liver damage

        2. Lipoxygenase / Leukotrienes
          1. 15- Lipoxygenase produces substances which appear to decrease Prostate Cancer . [132]

      5. Beneficial Health Effects of w-3 Fatty Acids5
        1. Physicians Health Study [Harris 82, 83]

          1. The Physician Health Study was a Population-based Case-Control Study that looked at Low
            Red Cell Omega-3 (EPA+ DHA Levels and Cardiac Death. The subjects in the highest
            quartile for (EPA+ DHA ) Levels in Red Blood Cells were at a 90% lower risk of Sudden Cardiac Death.
            ( JAMA 1995;274:1363-1367)
          2. It is the w-3 content that decreases Sudden Death , not the w-6 PUFA . Scientists suspect
            that the major benefit of fish oil and omega-3-fatty acid is in preventing ventricular fibrillation
            in event of a heart attack, as the Physician's health study found no association between omega-3-fatty
            acid consumption and risk of developing Non-fatal coronary heart diseases such as heart attacks
            without sudden death.


    7. Health Effects of Saturated( SFA ) vs Unsaturated Fats (PUFA /TRANS)

      1. Saturated Fat Good or Bad? [29a]

        1. Saturated Fats have better LDL / HDL Ratios than Trans Fats [139]


        2. Heart and Saturated Fats [136]

          1. Stearic Acid (c-18) and Palmitic Acid (c-16) , found in milk and meat products,
            are the preferred fuel for the Heart , and is why Fat around the Heart is Saturated. The
            heart draws on the reserve of fat in times of stress.
          2. Saturated Fatty Acids constitute at least 50% of cell membranes . They give
            membranes stiffness and integrity .
          3. Saturated Fat makes up only 26% of the Fat in clogged arteries plaques .
            The balance is Polyunsaturated Fatty Acids. Plaques have more w6- PUFA
            than AdiposeTissue does, high in LA and low in OA . [157]
          4. Saturated Fat lowers Lipoprotein(a) [LP(a)] whch lowers Heart Disease risk.
            High Lp (a) in blood is a risk factor for coronary heart disease ( CHD ),
            cerebrovascular disease ( CVD ), atherosclerosis, thrombosis, and stroke.
            High Lp (a) predicts risk of early atherosclerosis similar to high LDL ,
            but in advanced atherosclerosis, Lp (a) is an independent risk factor not
            dependent on LDL . [140]
          5. A study of post-menopausal hyperlipidemic women with a relatively
            low fat intake showed that a greater Saturated Fat intake was associated with
            less progression of Coronary Atherosclerosis . [132]
          6. A study of Portuguese males concluded that " Total Fat, Lauric Acid,
            Palmitic Acid, and Oleic Acid intake was inversely associated with Acute MI ,
            and a low intake of Total Fat and Lauric Acid from Dairy products
            was directly associate with MI. [132]
          7. The World Health Organizatio n has determined that there is "convincing" evidence : [138]
            1. Myristic and Palmitic Acid intake increases the probability of Heart Disease
            2. Lauric Acid has a "possible" risk for Heart Disease
            3. Stearic Acid has no increased risk at all for Heart Disease
            4. However, Lauric and Myrystic Acids have been shown to increase HDL in animal studies. [150b]
          8. "...despite decades of research, it is still a debatable proposition
            whether the consumption of Saturated Fats above recommended
            levels by anyone who's not already at risk of heart disease will
            increase the likelihood of untimely death. "
            ( Taubes , US Surgeon General 2001) [132]

        3. Breast Cancer and Saturated Fats [29k]

          1. Long Chain Saturated Fatty Acids ( LCSFA ) inhibit Breast Cancer Cell
            Proliferation. Long Chain Unsaturated . Fatty Acids ( LCUFA ) do not have this
            inhibition. This has also been demonstrated in Spontaneous and Transplanted
            Mammary Tumors in mice and rats, and in Breast Cancer Cell cultures .
          2. LCUFA added to LCSFA in small amounts did not affect this Tumor
            Supression , depending on the amount of LCUFA added.
          3. Stearic Acid increased Spontaneous Mammary Tumor Development Time
            in Mouse. This increase was not observed for Laurate (12) , Myristate (14) or
            Palmitate (16) , suggesting that Stearic Acid(18) inhibits Breast Cancer cell
            proliferation.
          4. OA and LA ( LCUFA ) show inconsistent Proliferation results. LA actually
            stimulates cell proliferation in cell culture models.
          5. DHA and EPA ( w3/ FO ) consistently shows inhibition of Cell Proliferation
            for Induced Mammary Tumors .

        4. Other Saturated Fat Effects

          1. Saturated Fat protects the Liver from ETOH and other Toxins , such as Tylenol!
          2. Saturated Fat enhances the Immune System .
          3. Short- and Medium- chain Saturated Fatty Acid s are Antimicrobial
            in the digestive tract.
          4. Long chain Omega-3 EFA are retained better in tissues when the diet is rich
            in Saturated Fat.
          5. Low Saturated Fat diets prevents Calcium absorption . At least 50% of
            dietary fat should be Saturated .
          6. Mice fed Coconut Oil (high in Saturated Fat) tended to be leaner than mice fed
            Soy Oil. [74]


    8. Health Effects of Particular Essential Fatty Acids

      1. LA Health Effects (Corn Oil) [99,99a-f,102-105,104]

        1. Cancer & LA
          1. Linoleic Acid (LA) enhanced, whereas w-3 fatty acids decreased, primary
            tumorigenesis . Linoleic acid also appears to be pivotal in the spontaneous
            metastasis of experimental tumors. In addition, Linoleic acid increased the
            proliferation of human breast tumor cells in culture. [99e]
          2. Linoleic Acid in high amounts is associated with more than a threefold greater risk of
            ER-negative Breast Cancer than ER-Positive disease (OR=3.48). [99a]
          3. Linoleic Acid stimulates the growth of T47D Breast Cancer Cells with an increase in
            the proportion of cells in the S phase . [105]
          4. Linoleic Acid binds to Estrogen Receptors and induce certain Estrogen
            Inducible Genes , creating an estrogen effect. [104]
          5. Cholesterol intake trends to a lower risk of ER-negative disease (OR=0.38)!

        2. Arteries & LA
          1. LA increases AA by 40% , LA and EDA by 400% in Endothelial Cells
          2. LA reduces PGI2, PGE2, PGF2a by 50-60% in Pulmonary Artery
            Endothelial Cells . AA+LA augments this reduction.
            (Does LA+AA increase disease?).
          3. TNFa increases PGE2
            1. TNFa + LA doubles IL-1, a potent inflammatory cytokine . [132]
            2. TNFa + ( SA or LNA ) does not have this effect.
          4. LA and OA both reduce cell Glutathione , increase Albumen Transfer ,
            increase Membrane Permeability , all inflammatory responses.
          5. Plasma and aortic plaques are rich in LA but low in OA [132]

        3. CHD & LA
          1. Linoleic Acid is considered pro-Inflammatory .
          2. A High-LA diet (Jewish-Israeli) showed a high CHD and Cancer Incidence
            compared to a Hi-OA /Olive Oil diet (non-Jewish Israeli). [132]
          3. 9,10-Epoxy-12- octadecenoic acid ( EOA ), a metabolite of Linoleic acid,
            causes cardiac arrest in dogs, probably thru increased Cardiac Arrythmias .
            Other metabolites of Linoleic Acid also have Toxic effects. [105c]
          4. The widespread public health support for a high Linoleic Acid intake is not
            borne out by the literature, as carefully scrutinized by Ravnskov . High
            Linoleic Acid intake is not associated with reduced all cause mortality ,
            as contrasted to high Linolenic Acid intake , which is. Epidemiology studies
            covering <2 decades are, at best, unconvincing about the benefits of high
            Linoleic Acid ( PUFA ) intakes. [102]
            1. Yam et al suggest that the Isreali Paradox - a high incidence of CAD,
              Cancer and other degenerative diseases in Israel - may well be related
              to high Linoleic Acid intakes.
            2. In 2 blinded clinical trials, Animal and Saturated Fat was compared to Corn Oil.
              Coronary events were less (27%) in the SFA group vs 48% in the CO
              group. The second found a reduction of CAD with increased LA that was
              offset by a doubling of the Cancer Rate in the second half of the trial,
              giving a Total Mortality that was unchanged .

        4. Inflammation & LA
          1. Linoleic Acid (but not Oleic Acid) upregulates production of Interleukin -8 by
            Human Vascular Smooth Muscle Cells via Arachidonic Acid Metabolites under
            conditions of Oxidative Stress. Preeclampsia is associated with Oxidative Stress ,
            elevated plasma levels of Linoleic Acid (LA ), and increased vascular smooth muscle
            expression of the inflammatory chemokine , Interleukin -8 (IL-8) . [105a]
          2. No previous population has been exposed to the current high intakes of
            LA thru Vegetable Oils and Soy- and Corn- based animal husbandry.
            We may be experiencing the " Linoleic Acid Paradox", in which a "healthy"
            Fatty Acid that lowers Cholesterol (LA) is associated with increasing rates
            of Cancer and Inflammatory and Cardiovascular diseases. Low intakes of
            ALA and other w3 Fish Oils in these studies compounds this paradox. [102]

        5. Metabolism & LA
          1. CPY1 and CPY2 P450 metabolize Linoleic acid to Monoepoxides . Linoleic
            Acid, Linoleic Acid monoepoxides and the corresponding diols are all cytotoxic .
            Monoepoxides and Linoleic Acid disrupt Mitochondrial Function . [105b]
          2. Linoleic Acid helps maintain membrane flexiblility . [75]
          3. International Society for the Study of Fatty Acids and Lipids ( ISSFAL )
            consensus recommends an upper limit of Linoleic Acid intake of 6.7 g/d
            (3% of energy). [102]


      2. LNA Health Effects (Fish Oil)

        1. CHD & LNA
          1. LNA consumption of 2-3g/day prevents Primary and Secondary CHD [92b,102]
          2. LNA vs Butter in Hamsters fed 12.5% lipids [5d]
            1. Linseed Diet lowered Cholesterol (-29%), LDL (-35%), HDL (-17%),
              Glucose (-20%), Insulin (-40%), and LDL / HDL ratios compared to the Butter Diet.
            2. LDL receptor concentration did not differ
            3. There is a gender difference.
            4. Note that LNA lowering levels does not mean that Butter raises levels.

        2. Breast, Colon, Skin Cancer & LNA
          1. LNA appears to decrease the risk of Breast and Colon Cancer , and the spread of
            Breast Cancer and Melanoma .

        3. Prostate Cancer & LNA
          1. Omega 3/6 Studies and Prostate Cancer
            1. One study in in Uruguay linked LNA with rapidly progressing Prostate Cancer
              and Macular Degeneratio n, increasing the risk 70% over control subjects (those that
              did not receive LNA ). LNA caused an increase in Prostate Cancer for those at
              highest LNA vs lowest LNA ( Deneo-Pellegrini , De Stefani et al) [92b,92e]
              1. They found that those with the highest intake of ALA ( alpha-linolenic acid,
                an omega-3 fatty acid precursor found at high levels in flax seed) had a
                440% increase in their risk of getting prostate cancer compared with those
                at the lowest level. The incidence of prostate cancer in Uruguay has increased
                by close to 80% in the last 50 years.
                The Uruguayan diet is comprised largely of meat (a major dietary source of
                LA, with some LNA ), dairy, and lots of food fried in cooking oils such as
                Canola oil (also a major dietary source of LA with some LNA ) – and
                virtually no flaxseed or unheated cold-processed flax oil . [92a]
            2. A Duke University Medical Center pilot study, published in the July 2001 issue of Urology,
              suggests that flaxseed, coupled with a low-fat diet, may help men reduce the
              risk of prostate cancer . The conclusions of the study were that even short-term changes
              to a high-fiber/flax supplemented diet resulted in prostate cancer cells that didn't divide as
              quickly as those in people not on the diet. And in men with early-stage cancers, a decrease
              in PSA levels associated with the cancer was also noted. [92a]
            3. A Korean study found that low ratios of serum omega-3 to omega-6
              polyunsaturated fats were associated with prostate cancer , ranging from
              0.89 for normal subjects to 0.71 for men with BPH to 0.50 for men with prostate cancer.
              The men with prostate cancer also had significantly higher levels of omega-6 acids
              than did the normal men and the men with BPH . The researchers concluded that
              their work supports the contention that omega-6 polyunsaturated fatty acids have a tumor-promoting effect while omega-3 acids have a protective effect .
              (Clinical Biochemistry, Vol. 32, August 1999, pp. 405-09). [92a]
            4. A large 2006 study found no association between total LNA intake and overall risk of
              Prostate Cancer. [92b]
            5. A 2007 study showed that 30 grams of flaxseed a day reduced prostate cancer growth [92f]

          2. Explanation and Consequences

            We have increased Omega-6 Linoleic Acid and decreased Omega-3 Linolenic Acid intake dramatically. Our diets now include huge amounts of highly refined oils that are extracted from plants and used for cooking or in prepared foods. These oils (such as corn oil, safflower oil, cottonseed oil, peanut oil, and soybean oil) are all high in the omega-6s . As a consequence, we have dramatically decreased our intake of omega-3's as found primarily in whole grains, beans and other seeds, and seafood – now getting our omega-3’s primarily as the secondary fatty acid in our highly refined bottled oils. [92a]

            1. We now get most of our omega-3s from foods that are ever higher in the omega-6 fatty acids, thus accounting for the increasing distortion of the fatty acid balance.
            2. The oils that we are consuming (even our omega-3s) have been heated to high temperatures in the process of refining them and in the process of cooking. As we will see later, this is particularly devastating.
            3. We have refined out the beneficial phytochemicals such as the lignans , which are an integral part of the oil complex, and which play a key anticancer role in the body
            4. Since we rarely eat fresh food anymore, we are also now consuming an ever-larger portion of rancid (oxidized) fats in our diets, which produces a large number of cancer forming free radicals in the body. (Note: The less saturated a fat is, the faster it will go rancid – a particular problem for vegetable oils.)

        4. Neurons & LNA
          1. Research has also suggested a major Neuroprotective effect of LNA in in-vivo models
            of both global ischemia and KA-induced epilepsy .

        5. Inflammation & LNA
          1. Dietary LNA (w3) decreases AA ( LNA blocks del4), but can increase release of
            AA in Pig Endothelium.

        6. Retina & LNA
          1. Polyunsaturated Fatty Acids derived from LA and LNA appear to be important functional components of photoreceptor cell membranes, although in equal dietary concentrations, LNA are more important . [146]

        7. DHA & LNA
          1. A Lo-LNA Diet (Peanut Oil/Hi-LA ) fed to rats lowered DHA levels in Uterus Phospholipids , raised DPA levels compared to Hi-LNA Diet ( PeanutOil /Hi-LA + Rapeseed Oil/ HiLNA ) . Uterine Growth response to low dose of Estradiol was less in the Peanut Oil group).

      3. GLA / DGLA (LA metabolites) Health Effects

        1. GLA and DGLA are mainly obtained from LA , which is then converted to GLA .
          GLA is further converted to DGLA , requiring Vitamins C, B3, B6, Zn, Mg. [90a]
        2. DGLA has major health benefits though, not GLA .
        3. Although most Americans obtain an excess of Linoleic Acid , often it does not
          convert to GLA because of metabolic problems caused by diets rich in
          sugar, alcohol, or trans fats from processed foods, as well as smoking,
          pollution, stress, aging, viral infections, and other illnesses such as diabetes.
          It is best to eliminate these factors when possible, but some prefer to supplement
          with GLA-rich foods such as borage oil, black currant seed oil, or evening primrose.
          1. Diabetics can't convert GLA to DGLA (del6desaturase inhibition). GLA supplementation
            improves nerve function and may prevent diabetic nerve disease. The recommended
            daily dose for diabetes it is 480 mg per day of GLA .
          2. Omega-6/ GLA supplements should not be taken with a seizure disorde r, since
            GLA increases seizures.
          3. GLA should not be used in pregnancy , for it may harm the fetus or induce preterm labor.
        4. Both AA and GLA induce Apoptosis in normal human skin fiboblasts , and abnormal lymphoblasts .
          1. Atopic Dermatitis is linked to lowGLA [92]
          2. Normal cells are least affected.
          3. WTK1-mutant p53 cells are most susceptible to the induction of Apoptosis ,
            independent of functional p53.
          4. Cell cycle progression was similarly affected, with normal fibroblasts arrested in S and
            G2/M phases after 48hour exposure to AA or GLA .


      4. OA Health Effects (Olive Oil)

        1. Breast Cancer
          1. Olive Oil (Oleic Acid, OA - Omega9) reduces Breast Cancer risk from 55 to 30% [132]
            1. Long-chain PUFA and LA had no impact on the OA reduction of Breast Cancer.
            2. This suggest that MUFA provides the Cancer benefit.
          2. Avocado and Soybean diets (LA& LNA - w3,w6 PUFA ) were Tumorogenic .

      5. EPA Health Effects (Fish Oil)

        1. EPA fed to mice reduced the mean tumor number of Intestinal Neoplasia
          by 68% vs OA controls.
          1. AA added to EPA abolished the tumor supression .
        2. AA and PGE2 were lower in normal Intestinal Cells when fed EPA .


  4. NATURAL-TRANS Fatty Acids: production in Cows
    from Dietary FA :

    1. CLA /TRANS Isomers of Linoleic and Linolenic Acids [73-7c,121-124j]

      1. Conjugated Linoleic Acid ( CLA ) is a mixture of isomers of LA , formed as an
        intermediate in the biohydrogenation of LA to SA in Ruminants.

        Example of a CLA: CLAc9,t11(w6)


      2. CLA is produced from LA , LNA , GLA and TVA through bioconversion in
        Rumen(1) and Breast Fat Tissue(2) . [ Kennelly 124]


      3. LNA and GLA bio-hydrogenate to CLAt9,c11 via TVAt11( Vaccenic Acid)
        and SA in the livestock Rumen.
        1. TVA accumulates in the Rumen(1) .
        2. CLA is also produced in the Rumen(1) as an intermediate via TVA .
        3. TVA is transported in the blood to Breast Adipose(2) tissue (the main site for its
          bio-conversion to CLAt9,c11 (via del-9desaturase enzyme) and other
          CLA Isomer s. [179]
        4. Over 86% of tissue CLA in Beef originates from desaturation of TVA in
          adipose. [124d]

      4. More than 12 isomers have been identified in milk and body fat from Rumens.

        1. CLA has two double bonds (isomers of Linoleic Acid). CLA's with one
          trans double-bond are bio-active .
        2. The CLA milk content varies throughout the year, higher in the spring and summer
          when cows are grazing most fresh material. Levels are lower from cows fed silage.
          The CLA content varies greatly from a low of 0.1% to a high of 2.0% or
          more of the milk, tissue or egg yolk lipids.
        3. Milk contains higher amounts of CLA than meat. This is probably related to the
          high-concentrate, low-fiber diets fed to finishing cattle in the United States which
          lowers CLA production.
        4. There is very low CLA levels in blood.

      5. CLA Major Isomers [121,124a,124f,132]


        1. CLA c9,t11 ( Rumenic Acid) is the major component of Milk Fat ( 80-90% Octadecadienoic Acid )
          and Rumen Products. CLAc9t11 is preferrentially incorporated into the phospholipids of cell
          membranes and considered anticarcinogenic . [129]
        2. CLA c9,t12 and TVA- Trans11 are considered to be beneficial for health
        3. CLA t7,c9 is the second most prevalent isomer of CLA in Beef Fat ( 8-15% of total CLA ).
          It has not been well studied and is often not reported. [121]
        4. CLA t10,c12 , although biologically active, is present in amounts less than 5% of the total CLA .
          LA (CORN Silage-based diet ) increases the amount of t10,c12 relative to c9,t11 to >90%.
        5. CLA c9,c11 is a cis-isomer that has not been well studied .


    2. CLA Health Benefits and problems

      1. Research suggests these general CLA benefits: [74]
        Increases metabolic rate
        Decreases abdominal fat
        Enhances muscle growth
        Lowers cholesterol and triglycerides
        Lowers insulin resistance
        Reduces food-induced allergic reactions
        Enhances immune system
      2. CLA is anticarcinogenic , antiatherogenic , antidiabetic , antiadipogenic . [124b]
      3. CLA reduces renal PGE2, inflammation and fibrosis . [131]
      4. CLA +Calcium reduces Pregnancy Induced Hypertension (8.3% vs 41.7%) in patients
        with a history of preeclampsia and a diastolic notch. [134]
      5. CLA has antiproliferative and antiinflammatory effects on colonocytes (Butyric Acid).
        There is little uptake of the CLA formed in the intestine, but it appears to have local effects on
        the intestines.[124c]
      6. Studies using mixed CLA isomers show reductions in total cholesterol, triacylglycerols
        and LDL in blood from humans. CLA [129]
      7. CLA induces a body fat loss that is enhanced in mice fed coconut oil (high is saturated fat). [74]
      8. CLAt10,c12 however, lowered men's "good" HDL cholesterol, raised their blood sugar,
        and made them more insulin resistant . [86] This may be do to CLA's anti-estrogenic effect. [74c,d]
        Note that a low fiber feed for rumen increases CLAt10,c12.


    3. Dietary Sources of CLA

      1. CLA content of Foods [74b]

      2. Eggs are rich in CLA , and it has been shown that the CLA in eggs survives the high
        temperatures encountered during frying.
      3. Cheese contains 80% of CLA as c9,t11 .
      4. Food products of grass-fed ruminants (e.g. lamb , beef ) are good sources, and
        contain much more CLA than those from grain-fed animals. [73,86]
        1. In fact, products from grass fed animals can produce 300-500% more CLA than
          from those fed the typical diet of 50% hay and silage, with 50% grain.
          Concentrations of CLA in the meat fat from Australia and Germany have 2-3x
          the levels found in US Cattle . [122]
        2. To achieve biological effects, the average human would need to consume 5gms/day
          of CLA . A single 3.5oz serving of grass-fed beef provides 1.2gms of CLA ,
          25% of this requirement. Convential grain-fed beef provides 0.5 gms
          or 10% of the CLA requirement for a positive effect. [86]
      5. Kangaroo meat may have the highest concentration of CLA when compared with other foods.
      6. Refrigerated storage and thermal treatment results in significant decreases or
        disappearance of some of the minor CLA isomers and a significant increase of trans,
        trans isomers. [126]


    4. Trans Isomer Production in Cows: Simplified Diagram



        CLA(c9,t11) and TVA(t11) are thought to have beneficial effects, while CLA(c10,t12) may
        contribute to health problems. Grass feeding increases the CLA(c9,t11) and TVA(t11) content,
        while Corn feeding increases the CLA(c10,t12) content.
    5. T11 path : EFA > TVAt11 & SA (in RUMEN) [121]

      LA: LA> CLA >TVA> SA
      LNA : LNA >TVA> SA
      GLA : LA> GLA >TVA> SA



      1. Rumen to Breast Bio-hydrogenation (t11) Pathways [122]


    6. T10 Path: EFA to CLAt10,c12 & SA (in RUMEN) [121]

      LA: LA> CLA > SA
      LNA : LNA > SA
      GLA : LA> GLA > SA



    7. CLA is synthesized de novo in Humans from LA and TVA (as in non-ruminents ),
      thru Intestinal Bacteria . [121]

      1. COLON metabolism of Fatty Acids is thru Bacteria.
        1. Dietary Fatty acids are mostly absorbed in the Duodenum .
        2. UFA are better absorbed than SFA .
        3. When Sugar-Beet Fiber is used as a food source for Colonic Bacteria, the primary
          products are the Saturated Fatty Acids Stearic and Palmitic Acid (60%) , and the PUFA
          Linoleic Acid and some Oleic Acid . The PUFA appear to be protected from metabolism
          to Saturated fats by incorporation into the bacteria membranes.
        4. When LA or LNA is added with sugar-beet , they are hydrogenated to
          Natural Trans products . The bacteria can hydrogenate LA and LNA , but not AA .
        5. The final product of LA metabolism in the Colon appears to be Stearic Acid .

      2. CLA /TVA Human Synthesis from Linoleic Acid (LA)


        1. Conjugated Linoleic Acid ( CLA ) production [124c]

          1. Linoleic acid(LA) ( cis - 9, cis - 12 18:2) is metabolized in the Human Colon
            (and in Rumen ). Humans have the del-9- desaturase enzyme ( VA/TVA> CLA ).

            1. t10, t11 Pathways in the Human Colon (and Rumen ).
              1. to Conjugated Linoleic Acids( CLA ) (mainly cis - 9, trans -11)
              2. to Vaccenic acid(VA ) ( trans- 11/18:1)
              3. to Stearic Acid (18:0)
              4. Other CLA isomers formed are the c9t11 , t9c11 , t9t11 .

            2. Hydroxy CLA Pathway in the Human Colon (and Rumen ).
              1. Linoleic (LA) is also metabolized to CLA Hydroxy Isomers via a
                second new 10- HydroxyCLA Pathway in the Human Colon and Rumen.
              2. LA converts to Ricolnoleic Acid ( RA OH 10c12 , an 18:1Fatty Acid) [6a]

        2. Stearic Acid ( SA ) production [124c]

          1. TVA and other t10 and t11 Path intermediates are bio-hydrogenated to
            Stearic Acid in the Rumen (see ahead).
          2. Oleic Acid is also biohydrogenated to Stearic Acid in the Rumen. It forms
            several Trans-c18 isomers, including TVA, during its biohydrogenation . It thus
            increases the production of CLA and TVA in Dairy products. The oils and seeds
            of peanuts, rapeseed, palm, coconut, hi-Oleic Sunflower which contain OA
            enhances CLA and TVA production.
          3. Stearate producing Bacteria in Rumen have been hard to find, because they
            are sensitive to the toxic effects of PUFA . The same may be true of Human
            Intestinal Bacteria .

    8. More Detailed Diagram Showing Milk Fat ( CLA /TVA) Synthesis:
      NATURAL-TRANS / UFA / SFA



    9. Ruminant Feedstuff Effects on CLA / TVA Milk/Meat content

      1. Forage and Concentrate feeds typically contain relatively small amounts of Lipids as Fatty Acids. [121]
        1. Forages contain mostly Phospholipids and Glycolipids , LNA and LA
          1. Forage Diets (Lo pH)
            1. Lo pH (5.5) has no double bonds beyond C10-16, increases OA > SA , and favors Trans11 Isomers. [179b]
            2. Pasture-fed Cow s in the summer have higher CLA milk content (2-3x the content of Mixed-fed
              winter or Concentrate-fed summer Cows).
            3. Hay Feed lowers TVA content compared to Corn Oil or rumen-protected CLA Feed.
        2. Plant Seed Concentrates contain mostly Triglycerides, LA and OA . [179b]
          1. Hi-Concentrate/Low fiber diets (Hi pH) fed to cows shifts from Trans11 to Trans10 isomers.
          2. Hi pH (6.5) favors C18 double bonds in C6 thru c16 positions. A high percentage of LA is
            converted to CLAt10,c12 rather than
          3. Plant Oils (sunflower, corn, soybean, canola, linseed and peanut) increase CLA content. [121]
          4. Supplementing feed with rumen-protected CLA reduces the conversion of
            TVA to CLAc9,t11 and may decrease del9desaturase in Adipose. [124d]
          5. LA converts to a high percentage of CLAt10c12
          6. LNA (Soybean Oil) added to LA feed increases Total Milkfat and content of
            TVA, CLAc9t11, LCFA , LA, OA , and SA and decreases content of SCFA and MCFA ,
            LNA and PA .This decreases the Saturated-to-Unsaturated FA Ratio and the
            Atherogenicity Index . Soybean oil fed at 3.6% of the diet raised CLA levels 5x. [124,124i]

      2. Oil additives affect Milk composition [121]
        1. TVA, LA, GLA , OA , LNA (grass) all increase TVA and CLA in milk.
        2. TVA decreases Saturated Fat in milk.
        3. EPA (Fish Oil) supplement increases CLA , DHA and TVA in milk, probably by inhibiting SA
          formation in the Rumen. EPA/ DHA (Fish Oil) added to Corn Oil (LA) or Grass-grazing increased CLAc9,t11
          in milk. [121]

    10. Milk/Butter Fat

      1. Basic Fatty Acid Content of Milk/Butter (Saturated/Polyunsaturated) [150a]


      2. DHA Longer Chain Content of Milk/Butter [121]

        1. Regular milk contains DHA at 0.06% of Total Fat. 250ml (8oz) contains 3mg for 2% milk, and
          5mg for whole milk.
        2. The US Institute of Dietary Medicine recommends that LNA intake should be 1.2% of Energy
          (2-4 gm/day). DHA +EPA is recommended to be 10% of Energy. This amounts to 127mg of
          DHA or EPA for adults, and 70 mg for children aged 1-3 years. If children aged 1-3 years drank
          two 8-oz glasses of whole milk, they would get 50% of the recommended intake of
          DHA +EPA .
        3. Milk can also be enriched with DHA by 3 times, containing DHA at 0.18% of Total Fat. 250ml (8oz)
          contains 10mg for 2% milk, and 16mg for whole milk.
        4. Recommended DHA +EPA is estimated at 200-400mg/day, although higher intakes
          may also be safe. The UK Government advises eating one to two portions of oil-rich fish
          per week, which will provide around 2-3g of the very long chain n-3 fatty acids.

      3. Butter Flavor [150a]
        1. The five primary factors responsible for Butter's flavor include:
          1. Fatty Acids
          2. Lactones
          3. Methyl Ketones
          4. Diacetyl / dimethyl sulfide

    11. Human Colostrum Fatty Acid Composition : [128]

      1. The ratio of Polyunsaturated to Saturated Fats was 0.6
        1. Monounsaturated Fats are 40%
          1. Saturated Fats are 38%
        2. Polyunsaturated Fats are 22%
          1. LA=15% , LNA =0.9% , AA=1% , DHA = 0.4%
      2. The ratio of w-6 to w-3 Fatty Acids was 8
      3. Dietary Fatty Acid composition affects the Lipid Content of Milk.
        1. Mothers consuming Organic Milk and Meat products have 50% higher
          Rumenic Acid (TVA) in their Breast Milk. [5a]
        2. Rats consuming CLA enriched Butter Fat had higher Mammary
          and tissue CLA , and lower rate of Mammary Tumors (-53%)


  5. Big Picture: Essential Fatty Acid Synthesis Interconversion Graphic :
    Saturated / MonoUnsaturated / Natural Trans / PolyUnsaturated Fatty Acids




  6. Food Oil Comparisons

    1. Oil Measure
      1. 1 tablespoon = ~ 15gms = 1/2 oz

    2. Fatty Acids in Vegetables Oils ( Bronner ) [158]


    3. Omega-3/Omega-6 Ratios in Whole Food (approximate) [38]


    4. Omega-3/Omega-6 Feeding of Livestock

      1. Eggs produced by Chickens fed a diet of
        Greens and Insects produce higher levels of Omega-3 Fatty Acids
        (mostly LNA ) than Chickens fed Corn or Soybeans . [37]
      2. Grain-Fed Beef has a Ratio of 4:1 Omega-6 to Omega-3
        Grass-Fed Beef has a Ratio of 2:1 Omega-6 to Omega-3 ,
        making it a better source of Omega-3. [41]
      3. The reason that grassfed animals have more omega-3s than grainfed animals is that
        omega-3s are formed in the green leaves (specifically the chloroplasts )
        of plants . Sixty percent of the fat content of grass is a type of omega-3 fatty acid
        called alpha-linolenic or LNA .
        When cattle are taken off grass and shipped to a feedlot to be fattened on grain, they
        lose their valuable store of LNA as well as two other types of omega-3 fatty acids,
        EPA and DHA . Each day that an animal spends in the feedlot, its supply of
        omega-3s is diminished . [41b]

      4. Lamb is almost always Grass-Fed , and subsequently higher in
        Omega-3 than other common meat sources. [37]
      5. Milk and Cheese from Grass-Fed Cows also good sources of
        Omega-3 . O ne UK study showed that half a pint of Milk
        provides 10% , and small piece of Organic Cheese
        provides up to 88% of the LNA requirements. [37]


    5. Corn Oil [102-103]
      1. Corn Oil is a poor source of LNA .
      2. Corn Oil (LA) decreases Saturated Fatty Acids and Cholesterol
      3. Spatial Learning [103]
        1. Fish Oil is better than CO in improving spatial memory in rats following recurrent
          pentylenetetrazole induced seizures.
          1. Rats fed dietary Fish Oil performed better than those fed Corn Oil in the Morris Water Maze ,
            a test used to examine Spatial Performance in rats.
          2. the FO group had shorter escape latencies during the escape test.
          3. the FO group stayed a longer time and swam a longer distance in the target quadrant in the spatial probe test.
          4. the FO group had higher brain DHA and lower brain DGLA and AA levels.
          5. the FO and CO groups did not differ significantly with respect to neuronal cell loss in the histomorphology study.
        2. FO and PCB have some similar effects on Spatial Learning in rat pups.


    6. Soybean Oil
      1. Soybean Oil has a high amount of Oxidation prone PUFA ( LNA +LA >60%).
        1. Soybean Oil is high in Vitamin E (anti-oxidant gamma-tocopherol)
        2. To produce Soybean Oil, the Soybeans are cracked, adjusted for moisture content,
          rolled into flakes, and solvent extracted with Hexane . The oil is then refined , blended
          and sometimes hydrogenated .
        3. Soybean, peanuts and other legumes replenish the soil with nitrogen and minerals.
      2. Hi-Oleic Soybean Oil
        1. HOSO contains more than 80% Oleic Acid, 2% Linoleic Acid, 3% Linolenic Acid and
          exhibits improved heat and oxidative stability over normal Soybean Oil.
        2. HOSO is resistant to Oxidation.
      3. Hi-Linolenic Soybean Oil (>50%)
        1. Genetic engineering also produces Soybean Oil with high levels of Linolenic Acid.
      4. Lo-Linolenic Soybean Oil (3 vs 7%)
        1. Lo-LNA Soybean Oil has less Trans Fatty Acids (10% vs 2.5% of energy) than
          Hydrogenated Soybean Oil.
        2. Lo-LNA Oil has less Saturated Fat than Partially-Hydrogenated Oil .
        3. Lo-LNA Oil resists Oxidation .
        4. Lo-LNA Oil has similar Free Fatty Acids to other traditional oils.
        5. However, Hydrogenated-Lo-LNA Soybean Oil has
          greater Free Fatty Acid content than Unhydrogenated-Lo-LA Soybean Oil
          and Partially-Hydrogenated Soybean Frying Oils .
        6. Newer varieties of Soybean have Ultra-Lo (1%) Linolenic Acid .
      5. Lo-Saturated Fat Soybean Oil
        1. Lo-SFA Oil has 8 vs 16% SFA .


    7. Olive Oil [164-179f]

      1. Olive Oil Categories [179d]

        Extra Virgin Olive Oil refers primarily to the acidity of the oil being less than 1%.
        In general, the lower the acidity the higher the quality of oil. Hi quality EVOO is from
        the first pressing of the olives, without using heat (a cold press) or chemicals, and
        has no "off" flavors. Today the vast majority of oil is made in continuous centrfugal
        presses. There is no second pressing.

        1. Extra-Virgin olive oil exhibits antioxidant properties , conserving all of the
          lipidic and antioxidant qualities of the olives. They contain high amounts of
          non-fats, including phenolic compounds and tocopherols (anti-oxidants).
          Extra Virgin is made from olives just like Virgin, with the only difference being
          the amount of acidity. Extra Virgin can have no more than 1% acidity.
          These oils have the highest levels of polyphenols and Omega-3 Fatty Acids,
          and the lowest levels of Saturated Fats and Omega-6 Fatty Acids.
          Hi Polyphenols give a longer shelf life .
          [Premium EVOO has FFA <0.3%, EVOO has FFA <1%]
        2. Virgin olive oils contain slightly less amounts of phenolic compounds and tocopherols .
          [ VOO has FFA <1.5%]

        3. Refined olive oil loses most of these beneficial properties during refining procedures,
          but retains a similar fatty acid composition as Extra Virgin olive oil . Over 50% of the oil
          produced in the Mediterranean area is of such poor quality that it must be refined to
          produce an edible product. No solvents are used to extract the oil; it is refined using
          charcoal and other chemical and physical filters
          [Refined has FFA <0.3%].
        4. Blended Olive Oil is a mixture of the refined oil with minor amounts of Virgin oil resulting
          in the typical green color and flavor similar to that of the Virgin oils. "Olive Oil" is blended
          with cheaper Refined oil and EVOO . It used to be call Pure Olive Oil . Light Olive Oil
          is highly Refined oil that has been steamed, bleached with peroxide, and then blended
          with small amounts of lesser quality virgin or extra virgin oil. Sometimes Oilve Oil is
          blended with Canola or other Vegetable oils. This should be stated on the label.Illegal
          blending of cheaper Hazelnut Oil can be profitable and is difficult to detect.
          [Blended has FFA <1.5%]
        5. Lampant , Crude, Olive-pomace oils are non-edible due to high Free Fatty Acid content.

      2. Olive Oil Quality

        Oils from fully ripe olives (black ), olives grown in poor soil , and olives grown in hotter climates
        have higher Saturated Fat and Lower Polyphenol concentrations than from unripe (green)
        olives or those grown in cooler climates . Tuscany and Umbria produce greener, more fruity
        and pungent flavored oils because these are harvested and produced from olives that are
        the most immature. Liguria , Provence, and Apulia have olives that are more golden in hue,
        are sweeter and have a nuttier flavor.

        1. EVOO has no Saturated Fatty Acids with greater than 18 carbon atoms.
        2. Olives contain Iron, Vitamin E and Copper
        3. Olive Oil has no Trans Fats
        4. EVOO gives higher Triglycerides than Refined Olive Oil, and raises Free Cholesterol in HDL .
        5. EVOO increases membrane OA in cholesterol esters and phospholipid esters
        6. EVOO improves glycemic control
        7. Early harvest oils often have a longer shelf because of the higher polyphenols and antioxidants,
          and are blended and are blended with late harvest oils to improve their shelf life.
        8. Green olives have slightly less oil, more bitterness and can be higher in polyphenols .
          The oil tends to be more expensive because it takes more olives to make a bottle of oil.
        9. Olives should be picked just before they ripen and milled the same day, as olives will begin to
          ferment within 3-4 hours after harvest. The best olive oils are made from those olives that have
          been harvested by being hand-picked or by beating the branches with a stick. It takes 1500
          to 2000 olives to make a quart of oil.
        10. Good Olive Oil should smell fruity. It shouldn't have an offensive odor. If it passes the nose,
          put it in your mouth. It should have a deep, Olive Oil flavor, a little bite to the throat. The taste
          should linger, all characteristics of EVOO . Sweetness, mustiness indicate an old product.
        11. The United States does not adhere to the International Olive Oil Council standards for olive oil.
          "Extra Virgin" may be applied to any grade of oil. The label "Cold-Pressed Extra Virgin" is
          not a guarantee of quality or composition. Whenever possible, choose expeller pressed,
          unrefined oils [97,168]

      3. Olive Oil Fatty Acid Content

        1. Olive Oil is 55-80% Oleic Acid , with <2.5% Free Acid, and may contain 5-20%
          Grape Seed Oil or Sea Buckthorn Oil .
        2. The PUFA content of Olive Oil varies from the Mediterranean Region,
          between 5 and 19%, with an average of 8% (as for Italian).
        3. EVOO has the highest natural content of MUFA ( OA ) which varies between 60-80% of total,
          depending on the species of olives. This makes it stable against Peroxidation . [166]
        4. Linolenic Acid content of OliveOil is less than 1%. There is no problem if levels are higher than
          that regarding nutritional value. But the International Olive Oil Society uses the Linolenic Acid
          the Linolenic Acid to establish the authenticity of the Olive Oil. Seed oils like Canola have
          higher levels of Linolenic Acid. More PUFA leads to a less stable oil. This is counterbalanced
          by the levels of antioxidants that protect the oil.

      4. Olive Oil (OO) Health Effects

        1. Oleic Acid, the main monounsaturated fatty acid of Olive Oil, suppresses Her-2/ neu ( erb B -2)
          expression and synergistically enhances the growth inhibitory effects of trastuzumab
          ( HerceptinTM ) in breast cancer cells with Her-2/ neu oncogene amplification. [179e]
        2. OO stimulates the secretion of bile and pancreatic hormones , and lowers the incidence of
          Gallstone Formation. [179f]
        3. Most of the dietary lipids in the Mediterranean basin, where consumption of Meat and Animal
          Fat is low, come from Olive Oil. Other diets rich in Chicken and Pork meats provide similar
          levels of Oleic Acid. [176]
        4. In animals receiving MUFA , Fat breakdown is greater and Insulin's Blocking of Fat Breakdown
          is Lower. Rats given PUFA as Soybean Oil had the opposite effect, lowering Fat Breakdown
          and raising Insulin's Blocking of Fat Breakdown.

      5. Smoke Point is the temperature at which oil starts to burn [169]

        1. EVOO smoke point is 406 degF
        2. Light Olive Oil smoke point is 468 degF , and is less costly to fry with.
        3. The smoke point varies with the Free Fatty Acid content of Olive Oil. The
          lower the Free Fatty Acid content, the Higher the Smoke Point.


        4. Hi Oleic Oils are engineered to have >90% OA . They perform well in medium to high heat
          applications, such as deep frying or high heat sauteing.
        5. EVOO Increases Resistance of LDL to Oxidation compared to refined . [179d]

      6. Olive Oil Categories [adapted from 168]


      7. OA metabolism [179]
        1. OA is a precursor for several trans-C18:1 in milk, including trans10 and trans9 and others,
          but trans10 predominates.
        2. OA > SA directly and via Trans monomers.
        3. OA does not convert to PA, LA, LNA in Rumen.
        4. OA > SA is increase with Lo ph in Rumen.
        5. OA >Trans is inhibited at low pH in Rumen.

      8. OA (Oleic Acid 18:1), LA( Linoleic Acid 18:2), LNA ( Linolenic Acid 18:3)
        Structure Comparison [179g]



    8. Flaxseed [92-92g,96]

      1. Flaxseed is cold-pressed Linseed oil without solvent extraction (no Erucic Acid)
      2. LNA content of Flaxseed varies from (52-70%), with covarying LA levels (24-3%)
        1. Humans must obtain LNA from their diet , because the 12- and 15- desaturase
          enzymes that make de novo synthesis from Stearic Acid are absent .
        2. Soybeans are the largest source of edible oils in the US, 40% of which is
          hydrogenated. All unsaturated fats produce Trans Fats when hydrogenated.
          Low-LNA Oils provide Trans Free alterrnatives , some produced by blocking
          the del6desaturase genes producing very low levels of LNA and LA, which are
          more resistant to oxidation.
      3. Flaxseed and its lignans appear to decrease Heart Disease and the damage
        from Rheumatoid Arthritis .
      4. Flaxseed (not the oil) also contains Phytochemicals , such as Lignans like
        Secoisolariciresinol , a Phytoestrogen and Anti-oxidant .
      5. Flaxseed reduces the growth and metastices of established ER-negative Human Breast
        Cancer in part due to its Lignan and FishOil components together, and not to decreased
        Lipid peroxidation (Free Radical formation)
      6. Flaxseed oil has a short shelf-life (weeks) even when refrigerated. Rancid oils contribute
        to Free Radicals and are Carcinogenic . Saturated Fats resist Peroxidation and rancidity.
        Anti-oxidants may prevent this.
      7. Flaxseed supplement increase Omega-3 body levels


    9. Canola Oil [98]

      1. Ca nadian O il L ow A cid = Canola
      2. Canola is part of the mustard family whose other members include Broccoli, Brussel Sprouts, Cabbage, Kale and Mustard Greens.
      3. Canola Oil is low in saturated fat, high in mon-unsaturated fat, with w3 and w6 essential fat.
      4. Canola Oil 19gms(1.5 tablespoons)/day lowers Cholesterol, which is supportive but not conclusive for a reduction in CHD .
      5. Canola Oil is obtained from Rapeseed Oil by removing the Euricic Acid which is implicated in Cancer and Rancidity, and Glucosinolates which are goitrogenic .
      6. Canola Oil is often used as a cheaper alternative to the healthier Virgin Olive and Grapeseed Oils. Although Canola has at least some Linoleic Acid content, supermarket varieties of Canola Oil are often refined and processed with chamicals and heat, which destroy much of its Linoleic / Linolenic Acids. Cold-pressed, unrefined Canola Oil is a healthier type of Canola (sometimes pricier than Virgin Olive Oil), and found primarily in health food stores and specialty markets.

    10. Peanut Oil

      1. Peanut Oil is a stable, high mono-unsaturate oil. Peanut Oil is available
        as a pure batch-pressed refined oil with a wonderful Peanut aroma.
      2. Peanuts and their oils may contain carcinogenic substances made by a fungus
        that grows in damp peanuts. The fungus can infest other damp grains and seeds,
        but peanuts are most susceptable because they grow underground.
        If peanuts are fungus free, the oil is fine.

    11. Cottonseed Oil
      1. Potatoes fried in Cottonseed Oil produce french fries that contain
        less Trans Fat than potatoes fried in Partially Hydrogenated Soybean Oil
        or Partially Hydrogenated Canola Oil.

    12. Palm Oil [179]
      1. Palm Oil is about 50% Oleic acid, similar to Olive Oil
      2. Palm Oil has higher levels of Palmitic SFA than Olive Oil.
      3. Palm Oil maintains desireable plasma levels of Cholesterol and HDL / LDL .


  7. Nutrient-Value vs Fry-Safety (Oxidation Resistance)

    1. Two competing characteristics of Fats for Cooking:

      1. Nutrient Content (more EFA , w3, etc.)
        1. Want more Mono-unsaturated Fats

      2. Resistance to Oxidation (Free Radicals, Trans Fat conversion)
        1. Heat Resistance
          1. Want less PUFA ( PUFA tend to oxidize)
          2. Want more MUFA and Saturated Fats. MUFA and Saturated
            Fats tend to resist oxidation , so MUFA +Saturated Fat content
            indicates oxidation resistance
        2. Microwave Resistance [52a]
          1. Microwave exposure does not affect Free Fatty Acid Percentage
            or Fatty Acid Composition
          2. The peroxide content of Virgin Olive Oil was lower than for other
            seed oils after Microwaving
          3. Trans isomers ( Linoleic + Linolenic Acid) were higher in Microwaved
            Corn Oil versus Safflower Oil.

      3. Examples of Oils to Obtain EFA Nutrition (Omega-3&6)
        1. Milk/Butter, Olive Oil, Fish Oil, Flaxseed Oil, Canola Oil

      4. Examples of Oils for Frying (Saturated Fat & Omega-9)
        1. Coconut Oil, Beef Fat(grass fed), Lard, Olive Oil, Palm Oil,
          Butter, Canola Oil, Peanut Oil (from highest to lowest heats)


    2. PUFA Content (NUTRITION)


    3. MUFA + SFA Content (FRYING)



  8. Saturated Fat Content of Oils [27]

    Differing Contents by Chain Length




  9. Omega Fatty Acid Content of Fats and Oils (Summary Table): [156-163e]



  10. Vitamin B12 (and Folate )

    1. Water Soluble Vitamin s [65]


    2. Cobalamin (Vitamin B12) Structure [67]

      1. Vitamin B12 is the largest vitamin, with a very complicated structure, but is water soluble. [60]





    3. Vitamin B12 Coenzymes [64]



    4. Vitamin B12 [22,60,63,67]

      1. In humans, B12 exerts its physiologic effects on two major enzymatic pathways.
        First, methyl-cobalamin (m-B12) is a cofactor in the conversion of
        Homocysteine to Methionine . This reaction is essential for the conversion of
        dietary and storage ( methyltetrahydrofolate ) folates to tetrahydrofolate .
        Second, adenosyl-cobalamin (aB12) is a cofactor in the conversion of
        Methylmalonyl coenzyme A ( MMCoA ) to Succinyl-CoA .

        1. B12 is required for growth , cell reproduction, hematopoesis , DNA
          and Myelin synthesis.
        2. Obtained only from meat, fish, eggs, dairy products, or sea algae
          1. Produced by microrganisms in the soil and sea
          2. Stored in the Liver, Kidney
        3. R-Protein , Intrinsic Factor and Stomach Acid are required for absorption
        4. Non-food supplement s provide a small percentage absorbed by diffusion
          without intrinsic factor
        5. Enterohepatic circulation may eliminate non-functional B12 analogues
        6. B12 crosses the blood brain barrier 3 hours after absorption and enters the brain
          bound to TransCobalamin II ( TCII ), thru an adsorptive endocystosis . There it is
          converted to its active Methyl and Adenyl forms .

      2. B12 Deficiency Syndromes

        1. B12 Clinical Deficiency: Signs and Symptoms [22,63,66]
          1. Lethargy
          2. Red Cell Anemia
          3. Thrombocytopenia
          4. Increased LDH
          5. Irritability, Depression , Hypomania , Personality changes,
            Memory loss, Diminished Intelligence, Dementia, Psychosis
          6. Decreased sensation , Loss of Bowel and Bladder control ,
            Optic Atrophy
          7. Dyspepsia : Patients with a B12 deficiency from H. Pylori infection showed an
            increased gastric emptying time of 230min, which decreased to 98min after
            treatment with B12- IM /PO for 80 days. The severity of Intestinal symptoms
            also went down 78%. [66]

        2. B12 Clinical Deficiency: Anemia and Neuropathy [22,63,67,71,72]

          1. Cobalamin deficiency causes a well known Megaloblastic Anemia and
            less known Neuropathies .
            1. Cobalamin neuropathy affects the Cerebral Cortex , Spinal Cord and
              Peripheral Nerves .
            2. Neuropsychiatric disorders , which are reversible with B12 therapy,
              may occur in elderly subjects without evidence of Anemia . This may be
              due to demylenation of peripheral nerves, the spinal cord, cranial nerves,
              and the brain.
            3. Adult B12 deficiency is distinct from Chilhood B12 deficiency.
          2. Folate deficiency causes an identical Anemia to B12, but does not appear to
            cause a direct Neuropathy.
          3. High Folic Acid levels combined with low B12 levels is surprisingly
            associated with significant cognitive impairment among the elderly
            in one study. [54c]
            1. A setup for DNA Synthesis without Methylation Reactions? (see
              B12 First Pathways ahead).
          4. Folate vs B12 Deficiency and Depression [69]
            1. Folate (B9) deficiency appears most connected with Depressive Disorders
              (low 5- hydroxytriptamine )
            2. Cobalamin (B12) deficiency appears most connected with Psychosis

        3. B12 Clinical Deficiency: Homocysteine [72a]
          1. Homocysteine is vasculotoxic .

      3. B12 Deficiency Factors: [23]

        1. Food-B12 Malabsorption is responsible for up to 50% of deficiencies,
          with Pernicious Anemia only a minority of cases. [66]
          1. This includes infection with H. Pylori
          2. Small intestine bacterial overgrowth in the elderly
          3. Antacids, proton-pump inhibitors (decreases stomach acid)
          4. Metformin , antibiotics, anti-convulsants
          5. Vegans at high risk ( enterohepatic circulation)
          6. High prevalence in elderly (up to 40%)
        2. Helobacter Pylori lowers B12 [54]
          1. Major cause of duodenal ulcers, gastritis
          2. Decreases stomach acid, exacerbating Vitamin B12 deficiency
          3. Serum H Pylori Antibody prevelance in Community Based Clinic:
            1. [B12 140-180] 92% HPylori seropositive
            2. [B12 180-250] 87% HPylori seropositive
            3. [B12 >250] 51% HPylori seropositive
        3. Antibodies prevent B12 absorption
          1. Anti-Parietal Cell Antibody
          2. Anti-Intrinsic factor antibody (Intrinsic Factor Blocking Antibody)
        4. Microwave Cooking / Food Processing lowers food B12 content [49-52]
          1. Microwave cooking causes appreciable loss of Vitamin B12 (~30-40% in 6 mins )
            in foods due to heat degradation
          2. Boiling milk for 2-5 mins has a similar degradation
          3. The major food form of B12, Hydroxy-Vitamin B12, degrades on microwave heating.
            The 3 degradation products of Hydroxy-B12 have essentially no activity
          4. Other milk and dairy processing reduces B12 activity: Ripened Hard Cheese/Yoghurt(40%),
            Cottage Cheese (82% - loss of whey)
        5. B12 and Nitrous/Nitric Oxide: General Anesthesia, Infection, Trauma [2-2d]
          1. Ado -Cbl and Me -Cbl forms of Cobalamin are very light sensitive, whereas CN -Cbl and H2O -Cbl are not. Photolysis of Ado-Cbl and Me-Cbl , sources of B12 at the cellular level, yields Aquocob (II) alamin , which combines rapidly with O2 or NO. The Co(II)- 02 complex oxidizes instantaneously to give Aquocob (III) alamin , while Co(II)- NO oxidizes slowly to give Co(III)-NO . The Co(III)-NO bond is very stable, with no dissociation noted after 24 hours at 23°C or 37°C or after exposure to bright light. Indeed, it was nearly impossible to break the Co(III)-NO bond.
          2. Abnormally high levels of NO may be produced in vivo in humans in various conditions, including infection , septic shock , and trauma , or after receiving Interleukin -2 for treatment of cancer. Also, NO (as a gas or as a prodrug ) is administered therapeutically transcutaneously , intravenously, orally, and by inhalation. In these circumstances, it is possible that the NO might diminish the enzyme cofactor abilities of Cobalamins and produce a functional vitamin BI2 deficiency state. also, loco-regional NO overproduction in critical sites might cause circumstances of compartmental vitamin BI2 deficiency .
            1. It appears the Aquo-Cobalamin [H20- Cbl ] may bind NO and quench its effects both in vitro and in vivo.
            2. The vitamin BI2 deficiency-like state noted with prolonged N20 administration is associated with an inactivation of Methionine Synthase . N20 causes dissociation of enzyme-bound Methylcobalamin with consequent diminution of enzyme activity as Nitrosylcobalamin is a poorer cofactor for Methionine Synthase than the native, unmodified H20- Cbl .
            3. Greenberg et al have shown that H20- Cbl might also quench NO effects in vivo. H2O-Cbl administered to mice could prevent or reverse endotoxin-induced shock . Mice receiving H20- Cbl and endotoxin had lower serum NO levels (nitrite/nitrate) and higher urinary NO, and their endotoxin-induced mortality was reduced. They believed that Nitrosylcobalamin was formed in vivo in the mice overproducing NO as a result of endotoxin injection, and that the Nitrosylcobalamin was being eliminated in the urine.
            4. It is possible that overproduction of NO in neural tissues as result of HIV-l infection could cause localized cobalamin functional deficiency, with resultant neuropathology consequences. These in vitro studies suggest that interactions between NO and cobalamins may have important consequences in vivo.
            5. Anti-leukemia activity of human macrophages involves the generation of Nitric Oxide (NO) derivatives. The NO induces a decrease in intracellular ferric iron levels, increasing Apoptosis of the leukemic cells.
              1. Addition of exogenous Iron reversed this NO-mediated inhibition of cell growth by elevation of intracellular iron, protecting leukemia cells from NO-mediated apoptosis .
              2. H2O-Cbl blocks the NO-mediated inhibition of HL-60 leukemia cell proliferation.
            6. Methylcobalamin was noted by Akaike et al to block NO-mediated toxicity for neural cells in vitro. It is likely that the Me-Cbl had been converted by light to H2O-Cbl.
            7. H20- Cbl has been noted to inhibit the abilities of NO to cause smooth muscle relaxation in vitro.
          3. Note that Nitrous Oxide is used in some dental procedures, and formerly was use for "twilight sleep" in labor.

      4. Lab Evaluation:
        1. Normal Serum B12 >400pg/ml
        2. False normal B12 levels with Active Liver Disease, Lymphoma,
          Alcoholism, Intestinal bacterial overgrowth
        3. Serum or Urinary MethylMalonicAcid ( MMA ) often increased in deficiency
        4. TransCobalaminII (TC-II) decreased in deficiency

      5. B12 Treatment
        1. IM or SQ injection 100 to 1,000 mcg every 1 to 3 months
        2. Oral dosing 500 to 2,000 mc g/d
        3. Sublingual forms 2,000 mcg/d
        4. Intranasal administration 500 mcg weekly

    5. Folate (Vitamin B9) [67,68]


      1. Sources of Folate

        1. Food Folate (transforms to 5- methylTHF ):
          1. In contrast to Synthetic FA (Folic Acid) , which is a monoglutamate ,
            Natural Food Folates are predominantly polyglutamates with a variable
            number of glutamate residues. It is estimated that approximately two-thirds of total
            Folate intake from a mixed unfortified diet is in the polyglutamyl form, derived mainly
            from vegetables. These polyglutamates need to be hydrolysed to the monoglutamate
            form for normal absorption in the proximal small intestine. [24
          2. This process is controlled by the intestinal brush-border enzyme glutamate
            carboxypeptidase II ( GCPII ). GCPII has a pH optimum at 6–7 and ingestion of
            foods that can change the intestinal pH may result in incomplete intestinal deconjugation
            of polyglutamyl Folates . For example, Tamura et al. (1976) have found a marked
            reduction in the bioavailability of heptaglutamate when added to 600 ml diluted
            orange juice in comparison with FA. The authors have established that the reduction in
            heptaglutamate bioavailability is as a result of the loweringof pH (to 3.7) by the
            high load of orange juice. Organic acid ions (citrate, malate , ascorbate and phytate )
            present in orange juice have a combined inhibitory effect on the activity of GCPII .
            Food Folates also have poor stability during cooking. [24]
          3. Food Folate is then rapidly converted and carried in the blood as 5- methylTHF
            ( N5CH3THFGlu1) , which readily enters cells and crosses the blood-brain barrier
            by active transport .
          4. 5- methylTHF must be demethylated in the brain to THF by the B12-SAM
            pathway, then polyglutamated (GLU5 vs GLU1) or it will exit the cell back
            into the CSF or bloodstream.

        2. Non-Food Folate (Folic and Folinic Acid):
          1. Folic Acid can correct DNA synthesis in blood cells .
            1. Non-food Folic Acid also enters blood cells, but bypasses the
              B12-SAM pathway , converting to THF (via DHFGlu1).
            2. Folic acid (FA), unlike N5CH3THFGlu1(from Food Folate ), can
              directly enter B12-deficient blood cells and resolve anemia
            3. Given in large doses on a continuous basis FA can maintain intracellular
              DNA synthesis , even when B12 is deficient.
          2. Folic Acid does not correct B12 neuropathy caused by impaired methylation ,
            since FA does not enter nerve cells .
            1. Folic Acid does not cross the blood-brain barrier
            2. The potential danger is that with Folic Acid supplementation in dietary staples
              such as flour, the incidence of B12 deficiency could rise, since the Folic acid
              corrected anemia masks the neurological deficit .
            3. In dividing cells (bone marrow), Folate becomes trapped as 5methylTHFGlu5
              ("Methyl Folate Trap") and SAH inhibits methylation .
              1. Brain cells would be afffected by this only if cells are dividing . ???
          3. Folinic Acid can produce methyl groups for DNA and RNA synthesis
            despite a B12 deficiency (see below).

    6. B12 Metabolic Pathways [55-72a]

      1. MethylB12 / Folate : First Pathways - One carbon (methyl) transfer (1) :
        1. Methylation Reactions [62]
        2. SAM/ Methionine Synthesis
        3. THF Synthesis
        4. Thymidine /DNA Synthesis



        1. SAM CYCLE
          1. Homocysteine is converted to Methionine [62]

            1. requires Methylcobalamin B12 , Methionine synthase and Pyridoxine
            2. requires THF cycle to regenerate 5- methylTHF
            3. Occurs in the Cytoplasm
          2. Methionine is converted to S-Adenyl-Methionine (SAM)
          3. SAM is primary for methylation of DNA, RNA, Protein, Lipid, and as a
            precursor to Polyamine Synthesis . [22]
            1. Transmethylation , Transsulfuration :
              1. Homocysteine is methylated to Methionine then to
                S-Adenosyl-Methionine (SAM)
                1. A methyl group is removed from SAM , is given up to produce SAH
                  ( S-AdenosylHomocysteine ), to Homocysteine , which is remethylated
                  to Methionine via Methionine Synthase (using methyl from Folate or
                  Folinic acid).
              2. Homocysteine can also be metabolized to energy In Peripheral Cells,
                but not in the Brain , thru Cystathionine and Cysteine ( transulphuration ) .
                The brain is thus totally dependent on the SAM pathway to
                metabolize Homocysteine .
            2. Neurotransmitter methylation :
              1. Involves carboxy-O-methyltransferase ( COMT )
              2. Depression/prefrontal function (norepinephrine, dopamine regulation)
              3. Extraneuronal epinepherine and norepinephrine degradation
                to metanephrine and normetanephrine
              4. COMT inhibited by high SAH / or B12 deficiency
              5. Tumor Necrosis Factor ( TNF )-programmed cell death induced
                by high SAH /B12 deficiency
            3. Phospholipid methylation :
              1. Influences membrane properties
            4. Protein Synthesis:

          4. SAM / THF CROSSOVER - Methionine Synthase

            Note that the SAM and THF cycles are linked at the Methionine Synthase
            Crossover, passing the methyl group from 5- methyl THF to Methionine :

            SAM PATH/ THF PATH Crossover

            1. Homocysteine > Methionine-CH3 (SAM cycle)
              5-CH3- TetraHydroFolate > TetraHydroFolate ( THF cycle)

          5. Methyl-B12 Deficiency:
            1. mB12 Deficiency: Homocysteine and 5- methylTHF can Accumulate

              First B12 SAM PATHWAY (mB12 dependent )
              1. Methyl-B12 deficiency allows Homocysteine (SAM) and 5- THF ( THF ) to accumulate
              2. In the brain, Homocysteine is reverted to SAH as it accumulates, with a fall in
                the SAM/ SAH ratio.
                1. SAH inhibits methylation reactions.
                2. SAH methylation inhibition varies from organ to organ.
                3. Homocysteine is vasculotoxic and neurotoxic , which may contribute
                  to neurological damage.
                4. Homocysteine also inhibits N-methyl-D-Aspartate receptors . [67]
            2. mB12 deficiency: Homocysteine Level can be Normal

              First B12 Accessory Pathway 1 :
              BETAINE PATH (B12 independent) [22]
              1. There is an another way that Homocysteine re-methylates directly
                back to Methionine , the Betaine Pathway (B12 First Path diagram).
              2. This path is independent of B12 , but requires THF . It may be important for
                Cholinergic function in the Fetus and in the Aged. It appears to be present in
                Liver, Kidney, Brain and Red Cells (see orange triangle in the First Cycles Diagram).

            3. mB12 Deficiency: Homocysteine Level can be Normal (periphery only)

              First B12 Accessory Pathway 2 :
              CYSTEINE PATH (mB12 independent ) [22]
              Homocysteine can also be metabolized to Propionyl-CoA in Peripheral Cells,
              bypassing Methinonine Synthase (thru Cystathionine ). This reducies
              Homocysteine Levels , providing a source of Energy.
              ( Propionyl-CoA in turns feeds into Fatty Acid metabolism, which requires
              aB12 , but not mB12 (see B12 Second Path ).


        2. THF CYCLE ( TetraHydroFolate )
          1. THF to 5,10- methyleneTHF to 5- methylTHF :
            1. Requires SAM cycle to regenerate Terahydrofolate ( THF ) from
              Folate or Folinic Acid to make Thymidine for DNA
            2. Occurs in the Cytoplasm
            3. Important in RNA synthesis:
          2. A detailed view of the THF Cycle [65]

        3. DNA ( THYMIDINE ) CYCLE
          1. Thymidine Synthesis/ Methylation (Cell Growth)
          2. does not require SAM cycle to regenerate Terahydrofolate ( THF )
            if Folinic Acid or Active Formate are available.
          3. Occurs in the Nucleus .

      2. AdenylB12: Second Pathway - Fatty Acid Metabolism (2) : [62]
        Methylmalonyl-CoA to Succinyl-CoA

        1. Beta Oxidation of odd -chain fatty acids , Homocysteine , Methionine
          1. requires Adenylcobalamin B12 (aB12) and Methylmalonyl-CoA mutase
          2. occurs in the Mitochondria
        2. Odd-chain Fatty Acids --> Propionyl-CoA --> Methylmalonyl-CoA --> Succinyl-CoA --> Succinate


          1. Get an excess of odd chain fatty acids
          2. produces GTP
          3. Normal Fatty Acid Oxidation
            Beta Oxidation of even -chain fatty acids does not require B12 [58]
            Even-chain Fatty Acids convert to Acetyl-CoA thru Beta Oxidation
            Even-chain Fatty Acids are metabolised to CO2 and water
            Even-chain Fatty Acids cannot convert to Glucose [55]

        3. Adenyl-B12 (aB12) Fatty Acid Metabolism Detail :
          Odd-chain FA, Branched Amino Acids, VitaminB1 and Cholesterol are
          metabolized to Succinyl-CoA . [22]
          1. Requires Adenyl-Cobalamin (aB12 )
          2. Propionyl-CoA converts to L-Methylmalonyl-CoA or MethylMalonicAcid ( MMA )
          3. L-Methylmalonyl-CoA converts further to Succinyl-CoA to enter to Citric Acid Cycle


        4. Adenyl-B12 Deficiency: Overproduction of MMA
          1. Accumulation of Propionyl-CoA , Methylmalonyl-CoA , MMA
            1. In Cbl deficiency, the conversion to Succinyl-Coa is impaired, leading to a build up
              of the intermediates Propionyl-CoA , D& L-Methylmalonyl-CoA , and thus
              increased MMA and Methylcitric Acid.
            2. Methylmalonyl-CoA inhibits Fatty Acid Synthesis (even & odd chain) [58a]
            3. MMA is rapidly converted to unkown compounds [22]
            4. There is an unimpressive correlation between MMA levels in
              the blood and/or urine and the severity of neurological disease.
              The accumulation of large amounts of MMA does not lead to central neuropathy in
              some patients [72]
          2. Accumulation of unusual odd-chain fatty acids in Nerve cell membranes
            may cause irreversable neurologic disorders [22]
            1. Propionyl-CoA / Methylmalonyl-CoA (which accumulates) add 3-carbon units
              to produce Odd&Branched-chain Fatty Acids (instead of 2-carbon units added during
              normal Fatty Acid Synthesis which produce Even-chain Fatty Acids).This may lead to
              Demylenation , but Neuro-Psychatric symptoms are not seen in situations with
              increased levels.
            2. Demylenation , Axonal Degeneration are seen both peripherally and centrally.
            3. Fronto and Fronto-Parietal Cranial Atropy in a 14 month old boy with
              severe dietary B12 Deficiency caused by his mother's vegan diet [61]
              1. B12 and uMMA excretion became normal 10 days after treatment began
              2. EEG was normal after 6 weeks
              3. Cranial MRI was normal after 10 weeks of treatment
              4. Cognitive and Language development was still impaired at 2 years of age,
                however.
            4. Window for reversal appears to be short (?months)
            5. There are no in vivo studies of biochemical and functional alterations of
              neuronal cells from B12 deficiency. [55]
          3. FDA decision to fortify cereals with Folic Acid may mask or accelerate
            neurologic features in untreated B12 deficiency , since the
            neurological features are not corrected by Folate ( Folate does not
            cross the blood-brain barrier).
          4. Folinic Acid (5- formyltetrahydrofolate (5- FTHF ) at 1-3mg/kg/day normalizes
            CSF 5- methyltetrahydrofolate (5MTHF). [65a]
          5. Elderly subjects with depression, lethargy, and memory impairment
            taking 50mg/week 7mg/day) improved visuomotor performance,
            visuospatial memory, logical reasoning, associative memory, and activities
            for daily living. [65b]

      3. Cell Locaton of SAM / THF , FATTY ACID Paths ( mB12 First and aB12 Second Pathways) [72]

      4. Fatty Acid Synthesis [59]
        1. Marrow and Mucosal Cells depend on SAM for growth.

      5. B12 Third Pathway - Other Neurologic Processes(3)

        B12 has hormone-like actions in the CNS [21,22,72]
        1. It appears that neuropsychiatric abnormalities are caused by decreased
          activity of a thrid mammalian B12- dependent enzyme .[22]
        2. Neurologic lesions in Cobalamin deficient rats are the result of an
          inappropriate release and/or synthesis of Neurotoxic Cytokine (s) and
          Neurotrophic Growth Factor(s ), both elicited by permanent B12 deficiency.
          1. Cobalamin Deficiency in rat CNS increases the production of a
            Myelin-damaging agent Tumor Necrosis Factor ( TNF-a )
            and decreases that of a Neurotrophic Agent
            Endothelial Growth Factor ( EGF ) .
          2. It follows that B12 plays a regulatory role in the normal
            mammalian CNS regardless of its coenzyme functions , since
            the severe neuro-damage caused by Cobalamin deficiency
            in the rat occurs as a result of a shift in the physiological equilibrium
            towards Neurotoxic Agents .
            1. The level of the biologically active form of TNF-a is higher
              in the Spinal Cord of TGX rats, which manifest Intramyelinic
              and Interstitial Edema.
            2. Permanent Cobalamin deficiency causes an absence of 4a
              EGF - mRNA in the Neurons and Glia of various CNS areas ,
              however the deficiency is induced.
          3. The chronic administration of B12 restores EGF-CSF levels
            and EGF mRNA expression in TGX rats in various CNS areas
            which have been studied.
        3. The Betaine First Accessory Path does not appear to play a role in
          neuropsychiatric abnormalities caused by B12 deficiency. [22]
          1. A Chicken-Vegan diet, without B12, would not prevent these
            abnormalites .


  11. The FLING Diet ®

      Take a look at the Nutrition Guidelines of the The FLING Diet ® which draws on
      these basic principles!

  12. References
    1. B12

      1)B12 Dietary Absorption - WIPO
      http://www.wipo.int/ pctdb /en/ wo.jsp ?IA=WO2002%2F067995& WO =2002%2F067995&DISPLAY= DESC
      2)Nitric oxide interactions with cobalamins : - M Brouwer 1996
      http://bloodjournal.hematologylibrary.org/ cgi /content/abstract
      http://bloodjournal.hematologylibrary.org/ cgi /reprint/88/5/1857. pdf
      2a)Nitric Oxide induces Apoptosis in Leukemia cells - H Ferry-Dumazet1 2002
      http://www.nature.com/leu/journal/v16/n4/full/2402404a.html
      2b)Subacute combined degeneration of the spinal cord after nitrous oxide anaesthesia - Beltramello
      http://jnnp.bmj.com/ cgi /content/full/64/4/563
      2c)MR findings in subacute combined degeneration of the spinal cord caused by
      nitrous oxide anaesthesia - I lniczky
      http://www.neuroanatomy.wisc.edu/ selflearn / SCD.htm
      2d) MRI of the Cervical Spine: Unusual Non-Neoplastic Disease - Basak
      www.medscape.com/ viewarticle /464850
      3)Analogues, Ageing and Aberrant Assimilation of B12 in Alzheimer's Disease - McCaddon
      http://content.karger.com/ ProdukteDB / produkte.asp ? Aktion = ShowFulltext & ArtikelNr =
      000051247& Ausgabe =227767& ProduktNr =224226
      4)Vitamin B12 Pathophysiology - Smith
      http://www.lifesave.org/VitaminB12Pathophysiology194-196. htm
      5)Testing for Bio-Active Vitamins - Food Product Marsili
      http://www.foodproductdesign.com/articles/462/462_0296QA.html
      6)Fatty Acid Oxidation - Biochemistry Berg
      http://www.ncbi.nlm.nih.gov/books/ bv.fcgi ?rid= stryer.section .3061#3065
      7)B12 Sources - Wantanabe 2007
      http://www.ebmonline.org/ cgi /content/full/232/10/1266
      8) Corrinoid (B12) Nomenclature - IUPAC-IUB
      http://www.chem.qmul.ac.uk/ iupac /misc/B12.html
      9)B12, B9 and Depression
      http://www.psycom.net/ depression.central.folate _B12.html
      10)Biosynthesis of B12 in Bacteria
      http://www.blackwell-synergy.com/ doi / pdf /10.1111/j.1432-1033.1993.tb18344.x
      11)B12 Absorption Spectra
      http://omlc.ogi.edu/spectra/ PhotochemCAD /html/vitaminB12.html
      12)B12 Transdermal B12 Patch
      http://www.b12patch.com/? gclid =CPStxvrAnpICFQGCxwod-hT5-w
      14)Microwave Menace - Soloman
      http://www.susansolomonmd.com/microwave_ menace.html
      15) Xray Structures of B12 Derivatives - Kratky
      http://www.uni-graz.at/che3www/ strubi /papers/full_text/ ruma / paper.htm
      16)Functional Adaptation of Ileal B12 Absorption in Man - A. M. Mackinnon
      http://www.springerlink.com/content/w17u24l174540157/
      17)B12 is a complicated Vitamin
      http://www.newscientist.com/article/mg13918904.300-the-assault-on-b12-the-gargantuan-task-of-
      unravellingnatures-route-to-vitamin-b12-is-almost-complete-
      18)B12 Optic Neuropathy
      http://grande.nal.usda.gov/ ibids / index.php ?mode2=detail&origin= ibids _references& therow =9345
      21)B12 Neurological Diseases - Singh Thomas E-Medicine
      http://www.emedicine.com/ neuro /topic439. htm
      22)Metabolic Abnormalities in cobalamin (vitamin b12) and folate deficiency 1993 - RH Allen
      www.fasebj.org/ cgi /content/abstract/7/14/1344
      23)50 Ways to Develop B12 Deficiency - Vegan Forum
      www.veganforum.com/forums/ showthread.php ?t=196
      24) Folate Bioavailability - McNulty
      http://journals.cambridge.org/production/action/ cjoGetFulltext ? fulltextid =902072

    2. FATTY ACIDS

      25) Fatty Acids
      http://en.wikipedia.org/ wiki /Fatty_acid
      26) Trans Fatty Acids
      http://en.wikipedia.org/ wiki /Trans_fat
      27) Saturated and Total Fat Contents Oils
      www.scientificpsychic.com/fitness/ fattyacids.html
      28) Hydrogenation/ Linoleic Acid
      http://www.chm.bris.ac.uk/ motm / linoleic / linh.htm
      29 )Future of Milk Fat Modification - O’DONNELL
      jds.fass.org/ cgi /content/abstract/76/6/1797
      29a- Trans Fatty Acids and Coronary Heart Disease: Background and Scientific Review
      Alberto Ascherio et al, Departments of Nutrition and Epidemiology ,
      Harvard School of Public Health
      ascherio1999.html (archive)
      29b- Cell Membrane Trans-Fatty Acids and the Risk of Primary Cardiac Arrest - Lemaitre
      http://www.circ.ahajournals.org/ cgi /content/abstract/105/6/697
      29c- Trans Fats: The Story behind the Label
      http://www.hsph.harvard.edu/review/ rvw _spring06/rvwspr06_ transfats.html
      29d- Trans fattyacids : are the effects only marginal? - W C Willett and A Ascherio
      http://www.ajph.org/ cgi /content/abstract/84/5/722
      29e- Trans Fatty Acids - Hydrogenated & Partially Hydrogenated Oils:
      http://www.recoverymedicine.com/hydrogenated_ oils.htm
      29f-Trans Fatty Acids - Information Food Science and Technology Trust Fund
      www.ifst.org/ uploadedfiles / cms /store/ATTACHMENTS/ tfas.pdf
      29g-Influence of Trans Fatty Acids on Health - Stendera
      http://content.karger.com/ ProdukteDB / produkte.asp ? Aktion = ShowFulltext & ProduktNr =
      223977& Ausgabe =229852& ArtikelNr =75591
      29h-Effects of Partially Hydrogenated Oil and Butterfat on Serum Lipoprotein- Almendingen
      http://www.jlr.org/ cgi /content/abstract/36/6/1370
      29i- Role of TFAs (trans fatty acids & other degenerated fatty acids) in Disease
      http://www.treelight.com/health/nutrition/ TFAsAndFasting.html
      29j- Saturated, Dietary Fats and Progression of Atherosclerosis - Mozaffarian , Knopff
      http://www.ajcn.org/ cgi /content/full/80/5/1102
      http://www.ajcn.org/ cgi /content/full/80/5/1175
      http://findarticles.com/p/articles/mi_m0CYD/is_13_39/ai_n6114090
      29k) Dietary Fat and Cancer - American Institute for Cancer Research
      Advances in Experimental Medicine and Biology Vol422
      http://books.google.com/books?id=PGGVzML7nUMC&pg=PA59& lpg =PA59& dq =Long+Chain+Saturated+
      Fatty+Acids+( LCSFA )+inhibit+Breast+Cancer+Cell&source= bl & ots =jH0RHoHhfb& sig =QBIYSzEj2PzYW-AcXszYTuTzhL8&hl=en& sa =X& oi =book_result& resnum =1&ct=result
      30 ) Stearic Acid Model
      http://www.3dchem.com/ moremolecules.asp ?ID=388& othername = Stearic %20acid
      31) Fatty Acid Metabolism
      www.jbc.org/ cgi /reprint/134/1/397. pdf
      32) Trans Fat Labeling
      http://www.cfsan.fda.gov/~ dms /qatrans2.html
      32b) Trans Fat History and Labeling
      http://www.hsph.harvard.edu/ nutritionsource /nutrition-news/ transfats /
      33) Trans Fat Biochemistry
      http://people.umass.edu/ ktheis / tfa.htm
      34) Trans Fatty Acids
      Ellin Doyle
      http://jchemed.chem.wisc.edu/Journal/Issues/1997/Sep/abs1030.html
      35) Trans Fat Fact Sheet
      http://www.nebeef.org/post/ lfu / Trasn _Fatty_Acid_Fact_ Sheet.pdf
      36 ) HDL / LDL ratio Fish Oil
      http://jlr.org/ cgi /content/abstract/36/6/1370
      37) Omega-3 Fatty Acids
      http://en.wikipedia.org/ wiki /Omega-3_fatty_acid
      Omega-3/6 Fatty Acid Ratio
      38) DHA /EPA Institute (Interesting**)
      http://dhaomega3.org/ index.php ?category=overview&title=Omega-6-to-Omega-3-Ratio
      Essential fatty acids in health and chronic disease.
      http://www.pponline.co.uk/ encyc /omega-3-omega-6.html
      http:// lib.bioinfo.pl / meid :38610 - A P Simopoulos
      38a) Metabolic Fate of LA, ALA, and LC-PUFAs
      http://www.fatsoflife.com/ pufa /intro_7.asp
      38b) DHA / TFA Infants
      http://dhaomega3.org/ index.php ?category=overview&title=Omega-3-and-Trans-Fatty-Acids
      http://dhaomega3.org/ index.php ?category=overview
      38c)Butter & Milk Fats
      What is Butter/Milk (Saturated, DHA /EPA)
      http://webexhibits.org/butter/ compounds-fatty.html
      http://www.livestocktrail.uiuc.edu/ dairynet / paperDisplay.cfm ? ContentID =286
      2H NMR studies of isomeric omega 3 and omega 6 polyunsaturated phospholipid membranes
      MA McCabe et al, Biochemistry. 1994 Jun 14;33 (23):7203-10 ( NMR Studies)
      http://www.unboundmedicine.com/ medline / ebm /record/8003485/abstract/2H_ NMR _studies_of_isomeric_omega_3_and_omega_6_polyunsaturated_ phospholipid _membranes _
      Essential fatty acids in health and chronic disease.
      AP Simopoulos et al, Am J Clin Nutr . 1999 Sep ;70 (3 Suppl ):560S-569S ( EFA in Health)
      http://www.ncbi.nlm.nih.gov/ pubmed /10479232
      38d) Hemp
      http://www.intensivenutrition.com/ hempoil.htm
      http://books.google.com/books?id=14ENix5RzMg&hemp
      www.drbronner.com/ pdf / hempnutrition.pdf
      39) LDL / HDL Ratios
      http://www.healthy-heart-guide.com/ cholesterol-ratio.html
      trans chol.pdf (archive)
      Membrane Structure
      40a http://www.cytochemistry.net/Cell-biology/membrane_ intro.htm
      40b http://en.wikipedia.org/ wiki /Cell_membrane
      41) Pocket Atlas of Nutritio n - Biesalski (good pictures, interesting)
      http://books.google.com/books?id=dKr4rwmptZwC& printsec = frontcover & dq =pocket+atlas+of+nutrition+ biesalski & sig =
      ACfU3U1UX50blGCbcEeAL4d6wc6NUIKlYQ#PPA111,M1
      41a) Omega-6 Fatty Acid
      http://en.wikipedia.org/ wiki /Omega-6_fatty_acid
      41b) Grass Feeding Benefits
      http://www.eatwild.com/ healthbenefits.htm
      http://www.americangrassfedbeef.com/ grass-fed-natural-beef.asp
      http://www.csuchico.edu/ agr / grassfedbeef /health-benefits/ index.html
      http://www.theatlantic.com/doc/200710u/beef-flashback
      http://jwest.biz/ blog /archives/2007_04_01_archive2.html
      grassfedbeach ross (archive)
    3. SUGAR

      42)Sugar Metabolism
      http://www.medbio.info/Horn/Time%201-2/carbohydrate_ metabolism.htm
      43)GLUT Transport Proteins and Monosaccharide absorption
      http://www.medbio.info/Horn/Time%203-4/glucose_transport_ proteins.htm
      http://www.vivo.colostate.edu/ hbooks / pathphys /digestion/ smallgut /absorb_ sugars.html
      44)Fructose and Obesity
      http://www.ajcn.org/ cgi /content/full/76/5/911
      44a) Treatment of Obesity with Calorically Unrestricted Diets - A. W. Pennington
      Am. J. Clinical Nutrition, Jul 1953; 1: 343 - 348
      http://www.ajcn.org
      45)Resistant Starch
      http://www.nutritionandmetabolism.com/content/1/1/8
      46)Sugar and Exercise
      http://grande.nal.usda.gov/ ibids / index.php ?mode2=detail&origin= ibids _references& therow =278373
      47) Glycolysis
      http://en.wikipedia.org/ wiki / Glycolysis
      http://en.wikipedia.org/ wiki /Fructose_2,6- bisphosphate
      48) Hexokinase
      http://www.pubmedcentral.nih.gov/ articlerender.fcgi ? artid =1265209
      C. J. Toews , Kinetic studies with skeletal-muscle hexokinase
      Department of Biochemistry, Queen's University, Kingston, Ontario, Canada
      Biochem J. 1966 September; 100(3): 739–744.
      48a) GLUT Transport Proteins
      www.medbio.info/Horn/ PDF %20files/glucose%20transport%20proteins.pdf
    4. VITAMIN B12

      49) wantanabe microwave B12 Jan 1998
      www.ncbi.nlm.nih.gov/ pubmed /10554220
      50) wanatabe microwave hydroxy-B12 Nov 1998
      http://pubs.acs.org/ doi /abs/10.1021/jf980727v
      51)Vitamin B6 deficiency
      http://www.naturalnews.com/02356.html
      Understanding Nutrition - Eleanor Noss Whitney, Sharon Rady Rolfes
      52)Vitamins in Food Microwaving Processing - Ball
      http://books.google.com/books?id=mcwdkygB0FQC&pg=PA280& lpg =PA280& dq =microwave+b12&source=
      web& ots =3lxzlP3f2o& sig =PkRkd6ZwAvYLDN9bSjVJpDfwKek&hl=en& sa =X& oi =book_result& resnum =1&ct=result
      52a)Microwave Heating of Fats
      http://www.actahort.org/books/474/474_139. htm
      53)Low Levels of Serum B12 may be related to Helicobacter Pylori Infection David Ball
      Journal of Clinical Gastroenterology
      http://www.docguide.com/news/ content.nsf /news/8525697700573E1885256CBA0024A344
      53a) Gastritis
      www.sh.lsuhsc.edu/ fammed / OutpatientManual / AdultGIProb.htm
      53b)Vitamin B12 deficiency and gastric histopathology in older patients - Dholakia KR
      www.wjgnet.com/1007-9327/11/7078. pdf
      54) The effects of increased folic acid intake among the elderly has benefits or harm
      depending on vitamin B12 level - Morris
      http://www.nutraingredients.com/Research/Folic-acid-effects-two-faced-depending-on-B12-levels-says-study
      55) Folate , vitamin B12, and neuropsychiatric disorders - Bottiglier T
      Nutr Review 1996 Dec; 54(12):382-90
      http://www.lef.org/protocols/abstracts/ abstr -077.html
      http://www.ncbi.nlm.nih.gov/ pubmed /9155210
      56) Sandyk R, Awerbuch GI
      Vitamin B12 and its relationship to age of onset of multiple sclerosis.
      Int J Neurosci . 1993 Jul ; 71(1-4):93-9
      http://www.lef.org/protocols/abstracts/ abstr -077.html
      57) Approaches to vitamin B1 2 deficiency (good overview**)
      Early treatment may prevent devastating complications - T. S. Dharmarajan , MD;
      http://www.postgradmed.com/ index.php ?art= pgm _07_2001?article=977
      58) Even-chain FA cannot produce glucose
      Fatty acid metabolism - Silva
      http://www2. ufp.pt /~ pedros / bg / fatty.htm
      58a) Handbook of Vitamins, p492 - Robert B. Rucker
      http://books.google.com/books
      59) The Effect of Vitamin B12 deprivation on the Enzymes of Fatty Acid Synthesis - Frenkel E, et al
      J of Bio Chem, 248(21):10Nov1973,p7540-46
      http://www.jbc.org/ cgi /content/abstract/248/21/7540
      60) B12 Cyanocobalamin(PI)
      www.apppharma.com/ PIs /59-PI_Cyanocobalamin_45813C.pdf
      61) Von Schenck 1997
      Persistence of neurological damage induced by B12 deficiency in infancy
      http://www.lef.org/protocols/abstracts/ abstr -077.html
      62) Vitamin B12 and Folate Metabolism
      www.dentistry.leeds.ac.uk/ biochem /lecture/ nutritio /Vitamin%20B12,%20folate,%20D%20%20powerpoint.ppt
      63) Vitamin B12 deficiency: Recognizing subtle symptoms in older adults ( excellent **)
      March 2003 Volume 58, Number 3 Geriatrics
      TS Dharmarajan , MD • GU Adiga , MD • Edward P. Norkus , PhD
      http://geriatrics.modernmedicine.com/geriatrics/Refereed+Clinical+Articles/Vitamin-B12-deficiency-
      Recognizing-subtle-symptoms/ ArticleStandard /Article/detail/50225
      64) Metabolism - An Overview ( excellent overview of Metabolism*)
      http://web.virginia.edu/Heidi/chapter18/chp18. htm
      Cobalamin Isomers
      http://web.virginia.edu/Heidi/chapter18/Images/8883n18_28. jpg
      65) Chapter 9 Water Soluble Vitamins
      http://faculty.fortlewis.edu/ byrd _s/Nutrition/lecture%20ppts/WatersolubleCh9. ppt
      65a) Psychomotor retardation with low 5- methyltetrahydrofolate in cerebrospinal fluid responding to folinic acid
      http://www.ncbi.nlm.nih.gov/ pubmed /12571785
      65b) Folic acid, ageing, depression, and dementia - E H Reynolds
      http://www.bmj.com/ cgi /content/full/324/7352/1512
    5. OVERVIEW VITAMIN B12

      66) Dyspepsia/Heartburn/Gastric Emptying
      Journal of Clinical Gastroenterology (2003;37:230-3)
      http://naturalfoodsmerchandiser.com/ ArticlePage / tabid /66/ itemid /1076/ pageid /5/ Default.aspx
      67) Donald G Weir and John M Scott
      Brain function in the elderly: role of vitamin B12 and folate
      British Medical Bulletin 1999; 55 (No. 3): 669-82
      http://bmb.oxfordjournals.org/ cgi /content/abstract/55/3/669
      68) Folic Acid
      http://en.wikipedia.org/ wiki /Folic_acid
      69) Folate , B12 & Depression - Goldberg ( Medline Search)
      http://www.psycom.net/ depression.central.folate _B12.html
      70) Subtle Vitamin-B12 Deficiency and Psychiatry: A Largely
      Unnoticed but Devastating Relationship?
      Med Hypothesis 1991, Dommisse J
      http://cat.inist.fr/? aModele = afficheN & cpsidt =11494835
      http://www.johndommissemd.com/site/965699/page/368501
      http://www.psycom.net/ depression.central.folate _B12.html
      71) The biochemical basis of the neuropathy in cobalamin deficiency.
      Weir DG, Scott JM .
      Baillière’s Clin Haematol 1995; 6: 479–97
      http://www.ncbi.nlm.nih.gov/ pubmed /8534958
      http://www.sciencedirect.com/science
      72) Subacute Combined Degeneration One Century Later.
      The Neurotrophic Action of Cobalamin (Vitamin B12) Revisited - Scalabrino , G 2001
      http://www.jneuropath.com
      72a) Homocysteine as a risk for vascular disease
      Nutrition Research Reviews (1998), 11, 31 1-338 - Weir
      www.journals.cambridge.org/production/action/ cjoGetFulltext ? fulltextid =593608
    6. CLA BENEFITS

      73)Conjugated Linoleic Acid ( CLA ) Wikipedia
      http://en.wikipedia.org/ wiki /Conjugated_ linoleic _acid
      74)Fat Loss - CLA reduces fat and preserves muscle
      Journal of Nutrition - Pariza
      http://thyroid.about.com/ cs / dietweightloss /a/ cla.htm
      http://www.sciencedirect.com
      74a)Grass-fed beef
      http://www.alderspring.com/health_benefits/html/ cla.html
      74b) CLA Health Benefits - U of Glasgow
      www.gla.ac.uk/media/media_79683_ en.pdf
      74c) CLA is anti-estrogenic - Liu
      http://www.ingentaconnect.com/content/ klu / brea /2005/00000094/00000002/00006942
      74d)Conjugated linoleic acid induces apoptosis through estrogen receptor alpha in human breast tissue - Liu
      http://www.biomedcentral.com/1471-2407/8/208
    7. EFA /PG

      75)Essential Fatty Acids
      http://www.dcnutrition.com/ fattyacids /
      76)AA pathyway
      http://www.arthritis.co.za/ arachid.html
      77)Prostaglandin Intro
      http://en.wikipedia.org/ wiki /Prostaglandin
      78)PG and Parturition
      http://www.jci.org/115/4/986?content_type=abstract
      79) CLA reduces PGF2a
      http://jds.fass.org/ cgi /content/full/89/10/3826
      80)Healthy Fats
      http://goodfats.pamrotella.com/
      81) LIver Damage by TXA2/ PUFA
      http://www3.interscience.wiley.com/journal/106599417/abstract
      82)Role of Omega-3 Fatty Acids in Cardiovascular Disease Prevention
      Physicians Health Study/ Cardiac Death
      William S. Harris PhD
      http://www.lipidsonline.org/slides/slide01. cfm ? tk =42& dpg =1
      83)Physician Health Study - Omega-3-Fatty Acids - Medicine.net
      http://www.medicinenet.com/script/main/ art.asp ? articlekey =23820&page=3
      Physician Health Study (website)
      http://phs.bwh.harvard.edu/
      83a) EFA
      http://en.wikipedia.org/ wiki /Essential_fatty_acid#Nomenclature
      84)Pulmonary Arteries
      TL Kaduce , AA Spector and RS Bar
      http://atvb.ahajournals.org/ cgi /content/abstract/2/5/380
      85)Metabolism by Human Colon Bacteria
      FAC Howard and C. Henderson
      Letters in Applied Microbiology 1999, 29 , 193–196
      www.blackwell-synergy.com/ doi / pdf /10.1046/j.1365-2672.1999.00616.x
      86) CLA Gut Bacteria Bio-synthesis
      E Devillard , F McIntosh, S Duncan, J Wallace
      http://jb.asm.org/ cgi /content/full/189/6/2566
      www.ncbi.nlm.nih.gov/ pubmed /10530040
      87) GLA /AA induce Apoptosis
      http://www.ncbi.nlm.nih.gov/ pubmed /9150372
      88) Lipoxin
      http://en.wikipedia.org/ wiki / Lipoxin
      89) CLA increases Lipid Peroxidation but not Atherosclerosis, Obesity
      http://jn.nutrition.org/ cgi /content/abstract/138/3/509

    8. GLA

      90a) GLA primer
      http://en.wikipedia.org/ wiki / Gamma-Linolenic _acid
      90) Beneficial Effects of GLA ( gamma-linolenic acid)
      http://pjstory.com/ GLA.htm
      91) Atopic Dermatitis Linked to Low É¡ - Linolenic Acid
      http://www.fatsoflife.com/ article.php ? nid =1&edition=this&id=578& issueid =65
    9. LNA - FLAXSEED & CANCER

      92) Linseed Oil
      http://en.wikipedia.org/ wiki /Linseed_oil
      92a)Flaxseed and Prostate
      http://www.jonbarron.org/newsletters/02/10-21-2002. php
      92b)ALA
      http://en.wikipedia.org/ wiki / Alpha-linolenic _acid
      92c)Flaxseed ER-neg Breast Cancer - Wang
      http://www3.interscience.wiley.com/journal/110478036/abstract? CRETRY =1& SRETRY =0
      92d) Foods, nutrients and prostate cancer: a case–control study in Uruguay
      http://www.nature.com/ bjc /journal/v80/n3/abs/6690396a.html
      92e) alpha-Linolenic Acid and Risk of Prostate Cancer - De Stefani 2000
      http://cebp.aacrjournals.org/ cgi /content/abstract/9/3/335
      92f)Flaxseed Halts Prostate Cancer
      http://www.medicalnewstoday.com/articles/72990. php
      92g)Flaxseed contains healthy Lignans
      http://www.montanaamber.com/flax_ information.htm
      92h)n-3 Fatty Acids and Health- British Nutrition Foundation
      http://www.nutrition.org.uk/ home.asp ? siteid =43& sectionid =626& subSectionid =31

    10. FATS

      93) Butter vs LNA
      Dietary Effects of alpha linolenic acid on cholesterol metabolism
      in male and female hamsters
      http://linkinghub.elsevier.com/retrieve/ pii /S0955286303001700
      94) LNA Uterine Effects
      http://jn.nutrition.org/ cgi /content/abstract/122/7/1529
      95)Peanut Oil
      http://www.herbs2000.com/h_menu/oils_ seeds.htm
      96)Unsaturated Fats
      http://www.answers.com/topic/unsaturated-fat
      http://en.wikipedia.org/ wiki /Unsaturated_fat
      97)Polyunsaturated Fats
      http://www.pccnaturalmarkets.com/health/1883000/
      98) Canola
      http://en.wikipedia.org/ wiki /Canola
      Facts about Canola Oil
      canola2WFM.pdf (archive)
      wholefoodsmarket.com

    11. LA

      99) LA info
      http://www.chm.bris.ac.uk/ motm / linoleic / linoleicc.htm
      99a) Er-negative breast cancer - Jakovljevic
      http://www.springerlink.com/content/xkfkylk6nqqk1fwp/
      99b) Postmenopausal Breast Cancer is associated with High intake of Omega-6
      http://www.jstor.org/ pss /3554025
      99d) LA stimulates Breast Cancer - Dietary Fat and Cancer
      Advances in Experimental Medicine and Biology Vol422
      http://books.google.com/estrogen receptors
      99e)Is there a relation between dietary linoleic acid and cancer
      Am J Clin Nutr 68 (1): 5 - Erickson
      www.ajcn.org/ cgi /reprint/68/1/5
      104) LA is Estrogenic - Liu
      http://www.ncbi.nlm.nih.gov/ pubmed /14974442
      http://linkinghub.elsevier.com/retrieve/ pii /S0944711304702901
      105) LA stimulates T47D breast cancer - Reyes
      http://linkinghub.elsevier.com/retrieve/ pii /S0304383503008516
      105a) Linoleic Acid, but not Oleic Acid, Upregulates Production of
      Interleukin -8 by Human Vascular Smooth Muscle Cells
      http://rsx.sagepub.com/ cgi /content/abstract/12/8/593
      105b)Analysis of the cytotoxic properties of linoleic acid metabolites
      http://cat.inist.fr/? aModele = afficheN & cpsidt =817919
      105c)Differential Effects of Linoleic Acid Metabolites on Cardiac - Harrell
      http://jpet.aspetjournals.org/ cgi /content/abstract/303/1/347
      120) Linoleic Acid
      http://en.wikipedia.org/ wiki / Linoleic _Acid
    12. ENHANCED SOYBEAN

      100) Enhanced Soybean Oils: Hi-Lo-Normal Level Omega Brochure
      http://www.soyconnection.com/soybean_oil/ pdf /2006oilsbrochure.pdf
      100b) Low-Linolenic Soybean Oil
      http://www.soyconnection.com/soybean_oil/ pdf /2006oilsbrochure.pdf
      100c)Food and Beverage Industry - Soybean Oil
      http://findarticles.com/p/articles/mi_m3289/is_11_168/ai_58162133
      100d)Soybean Oil
      http://www . soyconnection.com
      100e) Genetic Enhancement of Soybean Oil - AgBioForum
      http://www.agbioforum.org/v6n12/v6n12a04- cahoon.htm
      100f) High stearic , low alpha-linolenic acid soybean oil substiution for hydrogenated soybean oil
      http://www.ncbi.nlm.nih.gov/ pubmed /18365266
      100g) Frying performance of low-linolenic acid soybean oil
      http://cat.inist.fr/? aModele = afficheN & cpsidt =1300900
      100h) Soybean
      http://en.wikipedia.org/ wiki /Soybean
    13. COTTONSEED OIL

      101) Cottonseed Oil
      http://www.organicconsumers.org/ ge /kellog121505. cfm %20
    14. CORN OIL

      102) LA/ LNA benefits/ risks - Vos
      http://www.ajcn.org/ cgi /content/full/77/2/521
      103) Spatial Learning CO vs FO
      http://www.sciencedirect.com/science FO Spatial Learning
      http://toxsci.oxfordjournals.org/ cgi /content/abstract/57/1/102
      Effects of corn oil on spatial learning in rat - Solhju
      www.ingentaconnect.com/content/els/09284680/1998/00000005/90000001/art81140
      Differential effects of n-3 fatty acid deficiency on phospholipid molecular
      species composition in the rat hippocampus
      http://www.jlr.org/ cgi /content/full/43/4/611
      Arachidonic acid improves aged rats' spatial cognition.
      http://www.ncbi.nlm.nih.gov/ pubmed /15811397? dopt =Abstract
      http://www3.interscience.wiley.com/journal/118608858/abstract
    15. CLA BIOSYNTHESIS

      121)Biosynthesis of Conjugated Linoleic Acid ( CLA ): A Review - R.C . Khanal
      Pakistan Journal of Nutrition 3 (2): 72-81, 2004
      www.pjbs.org/ pjnonline /fin179. pdf
      122)Proceedings of the American Society of Animal Science - Bauman1999
      www.asas.org/ jas /symposia/proceedings/0937. pdf
      124)Milk and CLA Synthesis - Bell
      www.feedenergy.com/ ConjugatedLinoleicAcid.Bell.Kennelly .200x.pdf
      124a) CLA Penn State Primer
      www.das.psu.edu/dairy/dairy-nutrition/ pdf-dairy-nutrition /das0488cla.pdf
      124b) CLA Info Clarinol Supplement
      www.pcflabs.com/products/ pdf / CLA _Scientific_Background_ info.pdf
      124c) CLA Gut Bacteria Bio-synthesis
      http://jb.asm.org/ cgi /content/full/189/6/2566
      124d) CLA and CO on Beef Adipose
      http://jas.fass.org/ cgi /content/abstract/82/5/1419
      124e) Vaccenic Acid supplementation for Cows increases CLA and decreases Saturated Fats
      http://www.pathway-intermediates.com/static/ incept.php
      124f) CLA - the milk fat wonder - Bauman
      www.dairybusiness.com/northeast/June02/ pdf /F3%20p21%20CLA%20Milk%20Fat.pdf
      124g)Factors Affecting Conjugated Linoleic Acid ( CLA ) Content in Milk, Meat, and Egg:
      A Review - Khanal
      www.pjbs.org/ pjnonline /fin182. pdf
      124h)Increasing Amounts of Conjugated Linoleic Acid ( CLA ) Progressively Reduces
      Milk Fat Synthesis Immediately Postpartum in Cows
      http://jds.fass.org/ cgi /content/full/87/6/1886
      124i)Grazing Boosts Levels of Possible Cancer-fighter in Cows' Milk
      http://www.cals.wisc.edu/media/news/09_97/ CLA _in_ milk.html
      124j) CLA references
      http://www.wisc.edu/ fri /clarefs2004. htm
      124k) CLA
      http://www.fst.ohio-state.edu/People/HARPER/Functional-foods/Milk%20Components/Conjugated%20Linoleic%20Acids.htm


    16. CLA EFFECTS & HUMANS

      125) Bioconversion of vaccenic acid to conjugated linoleic acid in humans - Turpeinen
      http://www.ajcn.org/ cgi /content/abstract/76/3/504
      126) CLA-Fortified Dairy Products: Evaluation After Processing and Storage
      http://jds.fass.org/ cgi /content/full/90/5/2083
      127)Dietary trans-10, cis -12 conjugated linoleic acid induces hyperinsulinemia
      and fatty liver in the mouse
      www.jlr.org/ cgi /content/abstract/43/9/1400
      128)Human Colostrum
      http://content.karger.com/ ProdukteDB / produkte.asp ? Doi =47060
      129)Conjugated Linoleic Acid Differentially Modifies Fatty Acid Composition - Demaree
      http://jn.nutrition.org/ cgi /content/abstract/132/11/3272
      130) CLA and Grass-fed Beef
      http://www.alderspring.com/health_benefits/html/ cla.html
      131) CLA & Renal Disease
      http://www.nature.com/ ki /journal/v64/n4/full/4494013a.html
      132) CLA & Cancer, Atherosclerosis and Obesity
      http://findarticles.com/p/articles/mi_qa4035/is_/ai_n9390461?tag=untagged
      http://74.125.47.132/search?q=cache
      134) CLA & Hypertension
      www.partners-popdev.org/doc/reports/ AmJHypertens _2006_19_4_381. pdf
      135) CLA & Food Storage
      http://jds.fass.org/ cgi /content/full/90/5/2083

    17. SATURATED FATS

      136) Saturated Fat - Mercola
      http://articles.mercola.com/sites/articles/archive/2002/08/21/saturated-fat2. aspx
      http://articles.mercola.com/sites/articles/archive/2002/08/21/saturated -fat2.html [ ]
      138) Saturated Fat - Controversy
      http://en.wikipedia.org/ wiki /Saturated_fat
      139) Trans/Sat Fat LDL / HDL NEJM Ascherio 1999
      https://content.nejm.org/ cgi /content/extract/340/25/1994?ck= nck
      140) Lipoprotein(a) is a risk for cardiovascular disease
      http://en.wikipedia.org/ wiki /Lipoprotein(a)
      141) LA> CLA in Human Intestine
      http://jb.asm.org/ cgi /content/full/189/6/2566
      142) PUFA newsletter
      http://www.fatsoflife.com
      143) CLA supresses Colon Cancer
      http://www3.interscience.wiley.com/journal/118804219/abstract
      144) LA and Metabolites cause Cardiac Arrest in Dogs
      http://jpet.aspetjournals.org/ cgi /content/abstract/303/1/347
      145) Metabolism of Linoleic Acid
      http://cat.inist.fr/? aModele = afficheN & cpsidt =817919
      145a) Future of Milk Fat Modification - O’DONNELL
      jds.fass.org/ cgi /content/abstract/76/6/1797
      146) LNA important for Retinal Function
      http://www.sciencemag.org/ cgi /content/abstract/188/4195/1312
      147) CLA-enrched Butter reduces Cancer in Rats
      http://jn.nutrition.org/ cgi /content/abstract/129/12/2135
      148) FO +LA increases CLA and TVA in Milk
      http://jds.fass.org/ cgi /content/abstract/86/3/944
      149) CLA effects on Adipose
      http://jn.nutrition.org/ cgi /content/abstract/132/11/3272
      150) DHA /EPA content of Enhanced Milk
      http://www.hc-sc.gc.ca/fn-an/ gmf-agm / appro /dec104- eng.php
      150a) What is Butter
      http://webexhibits.org/butter/ composition.html
      150b) Butter Oil Properties Review [interesting*]
      http://www.greenpasture.org/products/butter_oil/properties
    18. TVA, CLA DISEASE ATHEROGENICITY
      151) Hi CLA effects on Atherogenicity
      http://www.ncbi.nlm.nih.gov/ pubmed /17992982
      152) Soybean Oil Feed to Goats Increases CLA
      http://jds.fass.org/ cgi /content/abstract/91/6/2399
      153) CLA isomers and Cancer
      http://jn.nutrition.org/ cgi /content/abstract/137/12/2599
      154) CLA Lipoprotein Effects
      CLA does not increases LDL
      http://linkinghub.elsevier.com/retrieve/ pii /S0021915005006702
      155) LA, Butter increase Lipid Peroxidation but not Atherosclerosis
      http://jn.nutrition.org/ cgi /content/abstract/138/3/509
    19. ESSENTIAL FATTY ACIDS

      156) Fat Content Foods
      http://curezone.com/foods/ fatspercent.asp
      157) The skinny on Fats (Price Foundation) good overview
      http://www.westonaprice.org/ knowyourfats / skinny.html
      158)Hemp plus
      http://www.sanihemp.com.au/web/ WhyHempSeedOil.html ? PHPSESSID =b98699cba5953725bc7b7c83a28cfa81
      158a) Nutritional Profile and Benefits of Hemp Seed, Nut and Oil
      http://www.drbronner.com/ pdf / hempnutrition.pdf
      159) Plant Seeds
      http://www.naturalhub.com/natural_food_guide_nuts_ common.htm
      160) DHA in Plant seeds/ GeneSplicing
      http://www.csiro.au/science/ps3u.html
      161) DHA Milk
      http://www.hc-sc.gc.ca/fn-an/ gmf-agm / appro /dec104- eng.php
      162)Peanut Nutrition
      http://www.nutritiondata.com/facts/legumes-and-legume-products/4357/2
      163) EFA /Andy Pryke
      http://www.andypryke.com/pub/ EssentialFattyAcids
      163a)EPA
      http://en.wikipedia.org/ wiki / Eicosapentaenoic _acid
      163b) DPA
      http://en.wikipedia.org/ wiki / Docosapentaenoic _acid
      163c) DHA
      http://en.wikipedia.org/ wiki / Docosahexaenoic _acid
      163d) DGLA
      http://en.wikipedia.org/ wiki / Dihomo-gamma-linolenic _acid
      163e)AA
      http://en.wikipedia.org/ wiki / Arachidonic _acid
    20. OA

      164) Conversion of Oleic Acid to Trans Isomers
      http://jds.fass.org/ cgi /content/abstract/88/12/4334

    21. EVOO

      165) Extra-Virgin Olive Oil Increases Resistance Of LDL To Oxidation
      http://findarticles.com/p/articles/mi_m0887/is_/ai_59017968
      166) Dietary extra-virgin olive oil with added omega-3 fatty acids - WIPO
      www.wipo.int/ pctdb /en/ wo.jsp ?IA=WO2004002234& wo =2004002234&DISPLAY=CLAIMS
      167) Olive Oil Primer
      http://en.wikipedia.org/ wiki /Olive_oil
      168) How Olive Oil Works - production
      http://recipes.howstuffworks.com/how-olive-oil-works2. htm
      169) The Real Story on OLIVE OIL
      http://www.diabetesincontrol.com/ results.php ? storyarticle =2508
      170) A taste for the extra-virgin olive oils - CASTRONOVO
      http://yudelstake.blogspot.com/2008/01/ taste-for-extra-virgin-olive-oil.html
      172) Linoleic Acid, but not Oleic Acid, Upregulates Production of Interleukin -8
      http://rsx.sagepub.com/ cgi /content/abstract/12/8/593
      173) EVOO are not creates equal
      http://www.elikioliveoil.com/ goodoloilish.html
      174) Definitions - The Olive Oil Source
      http://www.oliveoilsource.com/ definitions.htm
      175) Grandpa Po's Originals Definitions
      http://www.nutranuts.com/ definitions.html
      176) Olive oil: more than just oleic acid
      http://www.ajcn.org/ cgi /content/full/72/3/853
      177) Olives - WHFoods
      http://www.whfoods.com/ genpage.php ? tname = foodspice & dbid =46
      178) Olive Oil - WHFoods
      http://www.whfoods.com/ genpage.php ? tname = foodspice & dbid =132
      179) Olive Oil versus Palm Oil
      http://www.palmoiltruthfoundation.com/ index.php ?option=com_content&task=view&id=48& Itemid =78
      179a) Oleic Acid
      http://en.wikipedia.org/ wiki /Oleic_acid
      179b) Conversion of Oleic Acid to natural Trans Isomers pH Effects
      http://jds.fass.org/ cgi
      179c) Proposed Standards for Ollive Oil
      http://www.cooc.com/proposed_ standards.htm
      179d) EVOO increases resistance of LDL to Oxidation
      http://findarticles.com/p/articles/mi_m0887/is_/ai_59017968
      179e) Oleic acid, the main monounsaturated fatty acid of olive oil,
      suppresses Her-2/ neu ( erb B -2) in Breast Cancer cells
      http://annonc.oxfordjournals.org/ cgi /content/abstract/mdi090v1
      179f) Olive oil's health benefits
      http://www.healingdaily.com/detoxification-diet/ olive-oil.htm
      179g) Chemical and Nutritional Properties of Olive Oil
      http://www.oliveoilsource.com/ olivechemistry.htm
    22. HFCS

      180) CH20 carbohydrates 306
      http://wserver.scc.losrios.edu/~ropers/Chem%20306%20Chapter%2020%20Carbohydrates%20lecture%20outline.pdf
      181) Ch21 lipids 306
      http://wserver.scc.losrios.edu/~ropers/Chem%20306%20Chapter%2021%20-%20Lipids%20lecture%20outline.pdf
      182) Sucrose
      http://en.wikipedia.org/ wiki /Sucrose
      183) Carbohydrates
      www.elmhurst.edu/~ chm / onlcourse /CHM103/Rx16Bcarbo.ppt
      184) Cyclic AMP Fructose Uptake - Cui
      http://jn.nutrition.org/ cgi /content/full/134/7/1697/F3
      185) Fructose
      http://en.wikipedia.org/ wiki /Fructose
      186) Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity - Bray
      http://www.ajcn.org/ cgi /content/abstract/79/4/537
      http://www.ajcn.org/ cgi /reprint/79/4/537
      http://www.ajcn.org/ cgi /content/full/80/4/1090
      187) OurFood Database of Food and Related Sciences
      www.ourfood.com/ OurFood.pdf
      188) Glucose
      http://en.wikipedia.org/ wiki /Glucose
      189) Anomeric specificity of D-glucose metabolism in rat A dipocytes - Malaisse-Lagae
      http://www3.interscience.wiley.com/journal/120763043/abstract
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