Chester Clinic

Tf+ book-hennen-5th condensed version.pdf

Dietary Supplement Containing
Biologically Active Substances
For Improved Immune Function
William J. Hennen, Ph.D.
Dr. William J. Hennen holds a Ph.D in Bio-organic chemistry. An accomplished researcher,
professor and author, Dr Hennen hold more than 10 patents and has published over 30 research
papers and books in bio-organic, medicinal and nutritional chemistry.
Table of Contents
The Immune System
TABLE 1. MAJOR LINES OF IMMUNE DEFENSE TABLE 2. CHARACTERISTICS OF IMMUNITY The Acquired Immune System
INTRODUCTION: WHAT IS TRANSFER FACTOR? BENEFITS OF TRANSFER FACTOR SOURCES AND SAFETY OF TRANSFER FACTOR Innate and Adaptive Immunity Working Together
Microbial and Malignant Immune Evasion
IMMUNOLOGICAL AGENTS FOUND IN COLOSTRUM ZINC AND THYMUS SUPPORT AGARICUS BLAZEICORDYCEPS SINENSJS PHYTIC ACID, INOSITOI. HEXAPHOSPHATE, OR IP6 Olives and Olive Leaf Extract
OLEUROPEIN, HYDROXYTYROSOL, AND ELENOIC ACID Recent Immunological Testing on Supplements
ENHANCEMENT OF NK CELL ACTIVITY BY NATURAL AGENTS Appendix I. Human and Bovine Pathogens
AIDS, the very mention of the word causes visions of decimated persons, communities and even continents. The year 2000 estimates put the magnitude of the worldwide AIDS problem at 50 million infected, 6 million new cases ayear, 16 million dead, 10 million orphans with a projection of 40 million AIDS orphans by 2010.1 Sub-SaharanAfrica was reported to account for 2.6 million AIDS deaths in 1999 in a population that by some estimates includesone-third of its 15-49 year olds as HIV infected.2 These figures are especially disturbing when we remember thatHIV was unknown only two decades ago. As serious as these statistics are the information on Hepatitis C is evenmore disturbing.
Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and liver cancer worldwide.3 It is estimated that about 170 million people are chronically infected with HCV. 4 Hepatitis C virus(HCV)-related end-stage cirrhosis is currently the first cause of liver transplantation.5 Hepatitis C was firstidentified in 1989.6 The normal course of the disease runs 10-20 years.7 As Hepatitis C infections mature in agreater number of infected persons will become candidates for liver transplants, far outstripping the available supplyof transplantable livers. The spector of a black market in transplantable livers appears very real.
Not only are new and deadly diseases gaining power but antibiotics are beginning to fail us as antibiotic-resistant "superbugs" become a global problem."8 Even the foods we eat are not safe. In fact, over a dozen new foodbornepathogens have been identified in the last twenty years.9 The rapidity of air travel makes the most distant outbreakonly hours away.
Our immune system—an intricate, interrelated defensive force made up of a trillion cells-- is our protection from this deadly and daily onslaught.10 Our health, quality of life, and indeed our very survival, depend on theeffectiveness of our immune response. Today many factors contribute to the general weakening of our body'sdefenses. We will examine the nature of the immune system and consider the recent research on natural agents thatcan potentially save lives, thereby enabling us to make choices that can improve our health and protect us in anincreasingly dangerous environment.
The Immune System 11
Many times, however, our innate immune ability is insufficient against the variety of microbes we encounter daily. In these cases, our immune system has the ability to learn new skills and construct new tools to deal with thesemicrobial invaders. These immune responses are called adaptive or acquired responses.
"T cells" and "antibodies" are components of the immune system that are involved in adaptive responses. Once weare exposed to an infectious agent, our bodies destroy that agent by trying to identify it and react to it. This processtakes about ten to fourteen days. After we have successfully dealt with an infection, our immune system retains amemory of what it has learned about this particular microbial culprit so that the body is prepared if attacked again.
Typically, we are not even aware of subsequent exposures to the previously encountered microbe because ourimmune system responds so rapidly and with overwhelming force giving the microbe no opportunity to groweffectively. This adaptive response is the result of acquired immunity. This immune response is slow but normallyvery effective.
The Innate Immune System
The innate immune system is made up of various receptors, messenger molecules such as interferon, and natural killer (NK cells) which are our first-line defenders against cancer and infectious disease.12 The innate immuneresponse is characterized by the fact that it does not require prior exposure to an infectious agent."13 Further, theintensity of an innate response does not change when the system is repeatedly exposed to the same agent. The innateresponse works instead by recognizing distinct patterns in microorganisms and reacting to them.14, 15 Patternrecognition is innately coded into our immune system DNA and does not require us to have prior exposure to themicrobial agent.
There are remarkable parallels in the innate immune systems of widely separated organisms, indicating that these ancient defense systems are essential to survival.16 In the past, the innate immunity of vertebrates has beenconsidered archaic and obsolete, but today the innate immune system is regarded as essential to the function ofadaptive immunity.17 Natural antibodies are always present and do not require outside stimulus to appear. The main reason for theircontinual presence is their ability to target dangerous agents that are very common in the environment. Theseantibodies are not only produced by an effective immune system, but are also able to promote a more effectiveimmune response. After the initial identification of the microbial invader, other antibodies are elicited as a part ofthe adaptive immune response.
THE COMPLEMENT SYSTEM 18
The identification or tagging of the infected or malignant cell by an antibody is part of what's called the complementtagging process. The complement process is part of the innate immune system, and it provides the initial, ifincomplete, antimicrobial defense. The complement system serves three main functions: 1. Opsonization. This involves tagging damaged or infected cells that need to be destroyed and cleared from the
system.
2. Chemotactic response. The complement system sends out signals that mobilize immune cells and draw them to
the site of infection.
3. Membrane attack complex (MAC). MAC is formed to destroy tagged cells. Essentially, MAC is an assembly of
complement proteins that punch a hole in the lipid (fat) membrane of the invader, allowing water to rush in and burst
the membrane like an over inflated balloon. Some bacteria and cancer cells have an ability to destroy MAC if its
formation is slow, so MAC speed is essential.19
It is important to note that the cell membranes of animals are made up of two layers of lipids. Animal cells appear as a minute drop of water inside a bubble made up of two layers of fat. Because of this, many viruses wrapthemselves in a portion of the host's lipid membrane when they bud out from the infected host cell. By wrappingthemselves in a portion of host membrane, viruses protect their fragile RNA or DNA fragments within the lipidenvelope. The envelope also acts as a cloak, allowing the virus particle to evade the host immune system bymasquerading as a normal, albeit small, cell. Viruses that wrap themselves in host membrane are called envelopedviruses. A partial list of enveloped and non-enveloped viruses is shown below. As you can see, the list of envelopedviruses reads like a "who's who" of the most notorious viruses emerging today.
ENVELOPED AND NONENVELOPED VIRUSES 20
Human papillomavirus Enveloped viruses, unlike cells, do not contain membrane repair machinery. This weakness can be exploited bythe complement system. Even a tiny MAC prick will burst the viral bubble and destroy its infectivity.21 Clearlythen, the complement component of the innate immune system is critical in our ability to fight viral infections.
KILLER CELLS
The main function of immune cells like cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cells is destroying damaged or infected cells. CTLs receive their initial training in the thymus gland, which is part of theadaptive immune system and will be discussed later. However, NK cells, as mentioned earlier, are part of innateresponse. They target cells that are missing the self-marker that identifies a cell as one of our own.22 Foreign cellsdo not have such self-markers, and cancer cells often have lost their self- markers. Cells without self-markers areattacked by NK cells, while normal cells with high levels of self-markers are intentionally spared from NK cellattack.23 One could say that NK cells are like a National Guard battalion—they have roles in both defending againstforeign invaders and maintaining domestic order against seditious cells in the body politic.
A number of conditions are associated with low NK cell activity—cancer, acquired or congenital immunodeficiencies, chronic illnesses and infections, autoimmune diseases and several genetic and behavioraldisorders.24 The young, the old and the stressed are more susceptible to immunological breakdown. AugmentingNK cell activity may be critical in strengthening immunity in members of these groups. Laboratory findings indicatethat the young may have a reduced resistance toward cancer because of their diminished NK activity.25 NK cellsfrom elderly people show a decreased ability to multiply when stimulated and demonstrate an impaired killingcapacity. 26Stress from a variety of sources such as poor nutrition, emotional strain, infectious assault, cancer or injury willweaken the immune system's ability to learn new healing strategies. Inappropriate psychological reactions to stress,fatigue associated with chronic stress, and physical injury can lead to a disruption of immunity and suppressed NKcell activity.27 28 29 Continuous stress reduces NK activity and allows tumors to grow faster.30 Individuals with lowNK cell activity also tend to experience more frequent and severe forms of chronic fatigue immune dysfunctionsyndrome (CFIDS).31 Without functionally efficient NK cells, other cells of the immune system are not optimallyactivated.32 Dietary supplements that enhance NK cell activity may be critically important.
The Acquired Immune System
Acquired immunity is the result of immune system adaptation to new pathogens that have invaded the body. In order to adapt to these newly introduced threats, the immune system must first recognize the threat, then develop aset of specialized tools and finally, maintain a long-term memory of the organism to protect against possible re-infection. Four critical components of acquired immune response are essential to its proper function. They are (1)the thymus gland and T cell development, (2) antibodies, (3) cytokines and (4) transfer factor.
THE THYMUS AND T-CELL DEVELOPMENT
The education of immune cells can be compared to a school system having grammar school, prep school, college and graduate level training. The thymus gland is the grammar and prep school for three groups of immune cells.
Because of the involvement of the thymus, these cells are called T-cells. They include helper T-cells, suppressor Tcells and cytotoxic T-cells (most often called cytotoxic T-lymphocytes).
Each type of T-cell has its own particular function. Helper T-cells assist the other immune system cells in performing their important functions. Suppressor T-cells control immune response and keep the immune systemfrom overreacting. Both helper and suppressor T-cells perform their function by working indirectly through otherimmune cells. Cytotoxic T-lymphocytes, however, act directly on offending cells. CTLs are programmed in thethymus to look for self-markers and foreign markers. A combination of markers on the same cell identifies it as oneof the body's own cells that has been damaged.
The immune training functions of the thymus gland are weak in infants and increase in strength until puberty.
After puberty, the thymus gland begins to shrink and continues to diminish in size and effectiveness throughout the rest of our lives. The reduced training of T cells by the aging thymus is thought to be responsible for the immunedeficiencies that develop during aging.33 It is the job of the thymus to help us react against foreign cells and notagainst our own normal cells. As the thymus shrinks, the body's normal immune response to foreign cells weakens,while the autoimmune attacks on our own tissues becomes stronger. This situation is called the aging paradox.34 Incompetent thymic training produces T-cells that are unable to adequately interpret the immunological messages they receive from their environment. Dietary supplementation that supports the thymus and improves T-cell functionresults in a cascading improvement in the overall immune response.
Antibodies are protein molecules produced by B-cells. Natural antibodies react against the most common features of the most common pathogens. Natural antibodies are so important that they are coded into our DNA andare part of our innate immune system. This is only a small portion of our total antibody repertoire. We acquire mostof our antibodies as a result of a process of immune recognition and reaction. This process usually takes 10 to 14days to mature. Structurally, antibodies have claw-like features that allow the antibody to seize unto foreignmicrobes or damaged cells. Once the antibody has attached itself to an offending cell, the rest of the immunesystem reacts by attacking the tagged cell and destroying it.
MACROPHAGES --"BIG EATERS"
Macrophages ("big eaters") are large immune cells that engulf and degrade foreign, dead or damaged cells. If the engulfed cell is infected or malignant, the macrophage retains intact any new foreign sequences that can be used asantigens. Antigens serve as recognition markers used by the immune system--to stimulate antibody production.
Macrophages then act as antigen-presenting cells, which means that the macrophages present the newly discoveredantigens in a form that T-cells can recognize. Once this has occurred the immune system can then initiate anadaptive immune response to eliminate any other foreign or cancerous cells.
Memory T-cells and B-cells are produced by the immune system as a means of storing the immunological information that has been gained by the host. Because of its memory capacity, the response of the immune systemduring the second exposure is usually so effective that we are not even aware that we have been re-exposed.
In addition to producing cells, the immune system produces a host of messenger and control molecules known as cytokines. Cytokines play important roles in all phases of immune response. Some cytokines act as mediators ofinnate immunity, while others are involved mainly in acquired immunity. In the latter case, cytokines control theactivation, growth and differentiation of cells. Transfer factors may be among the most important cytokines.
Transfer Factor (TF)
INTRODUCTION: WHAT IS TRANSFER FACTOR?
While studying tuberculosis in the late 1940s, Dr. H. Sherwood Lawrence, discovered that the immune competence of a donor could be transferred to a naïve recipient by using low molecular weight extracts obtainedfrom white blood cells.35 Dr. Lawrence called these small molecule extracts transfer factor (TF). If the thymusgland can be compared to grammar school and prep school, transfer factor can be compared to collegiate andgraduate level training for the immune system. The importance of a more sophisticated, immunological educationshould not be underestimated. Scientists later found transfer factors to be universally effective, regardless of thedifferences between the species of the donor and recipient. This aspect of transfer factors is partly explained by thiscore scientific belief: the more essential a material or structure is to living organisms, the more common it is to seethis material or structure throughout living systems. Transfer factors are essential components of even the mostprimitive immune systems.36One basic principle of the immune system is that it must be able to respond quickly and specifically, while not exhausting itself by over responding and attacking normal tissue. Transfer factor preparations consist of threeidentifiable fractions named by their discovered effects on the immune system. They are inducer, antigen specificand suppressor fractions.37 The TF inducer fraction triggers a general state of readiness in the immune system, andthe antigen-specific fraction is an array of critical tags used by the immune system to identify a host of enemymicrobes. Meanwhile, the suppressor fraction keeps the immune system from focusing all its strength on a defeatedinfection and ignoring new microbial threats; it is responsible for controlling immune overreactions that can causeautoimmune disorders. Each fraction (inducer, antigen specific, and suppressor) improves one or more aspects of theadaptive ability of the immune system.
As the product of a competent immune system, transfer factor can teach a less competent immune system how to better respond. For example, mammalian mothers transfer immunity to their offspring through the colostrum in theirmilk. A mother's gift of transfer factor greatly improves the immunity of her offspring and many times means thedifference between life and death for the newborn. The modern dairy cow is in intimate microbial contact with herenvironment., Because of this and because she produces so much colostrums, she also produces far more transferfactor than her calf needs. Harvesting the excess colostrum and isolating its transfer factor provides an abundant andbeneficial source of transfer factor for human consumption.38 Unlike antibodies that are large molecules, transfer factors are quite small.39 In fact, their small size helps to make them nonallergenic.40 And while antibodies are used up when they attach themselves to the offending cell orprotein, transfer factors perform a different role. They are immune messenger molecules that educate and alert naiveimmune cells to an impending danger. In this regard, transfer factors perform a catalytic role in the immunesystem—triggering the effect without being consumed.41 Originally, transfer factor preparations were administered by injection.42 However, later studies showed that transfer factor was equally effective when taken orally.43 The nonspecific inducer and suppressor fractions oftransfer factors are fully compatible between different species. The antigen-specific transfer factors are each specificto a particular pathogen and these pathogens vary from species to species. An example might help illustrate thepotential benefit of antigen specific transfer factors in recipients of a different species than the donor.
Although the highly contagious and often fatal disease of smallpox devastated many European and American communities in the 1700s, one subset of individuals seemed to survive the epidemics—milkmaids. Milkmaids oftencontracted cowpox from infected animals during milking through a cut or break in the skin. Milkmaids infected withcowpox usually followed a mild course of the disease that was resolved without much difficulty. It was then foundthat milkmaids who had contracted cowpox were immune to smallpox. In a classic, early inoculation experiment,Edward Jenner vaccinated a young boy with cowpox and then demonstrated that the child was protected fromcontracting smallpox. The relationship between smallpox and cowpox is a case of antigen crossover where theimmune system recognizes two different pathogens after being exposed to either one. Antigen crossover between theof human and bovine pathogens is highly likely. (Appendix 1 contains a more complete list of human pathogens andtheir related bovine pathogens). The antigen-specific, bovine transfer factors should therefore provide protection tohumans against the corresponding human pathogens, resulting in a milder course of disease.
BENEFITS OF TRANSFER FACTOR
The exciting benefits of transfer factors—the essence of the immunological message, could spark a revolution in medicine. The need for such a new weapon in our immune defense arsenal is clear. "Transfer factor [has] animportant role to play in modern medicine which, from AIDS to Ebola, faces the emergence of new viruses or theresurfacing of old pathologies such as tuberculosis."44 Nevertheless, there are always many who resist new ideas,regardless of the their benefits. In a recent international symposium on transfer factors, Dr. D. Viza summarized thisconventional resistance: At the end of the 20th century, the triumph of biology is indisputable… triumph of biological science is far from being complete. The toll of several diseases, such ascancer, continues to rise and the pathogenesis of AIDS remains elusive.
In the realm of inductive science, the dominant paradigm can seldom be challenged in a frontal attack, especially when it is apparently successful, and only what Kuhn calls ‘scientificrevolutions' can overthrow it. Thus, it is hardly surprising that the concept of transfer factor isconsidered with contempt . . [since] its putative mode of action contravenes dogmas of bothimmunology and molecular biology. And when facts challenge established dogmas, be [it] in religion, philosophy or science, they must be suppressed. …because they challenge the prevalentparadigm. However, when observations pertain to lethal disorders, their suppression in the nameof dogmas may become criminal. Because of the failure of medical science to manage the AIDSpandemic, transfer factor, which has been successfully used for or treating or preventing viralinfections, may today overcome a priori prejudice and rejection more swiftly.45 The benefits of transfer factor have been reviewed and the proceedings of the Tenth International Symposium on Transfer Factor have been published.46 47 48 These reports cover the successful use of transfer factor in addressingviral, parasitic, fungal, malignant, neurological and autoimmune diseases. Transfer factor has been shown to bebeneficial to all age groups, from children to the elderly. The benefits from human use of animal-derived transferfactors have been repeatedly illustrated. In like manner the efficacy of the oral administration of transfer factor hasbeen demonstrated. In most of the published research on the use of transfer factor, disease and malaise werepresent, but the real power of transfer factor is actually in prevention. The use of transfer factor in the prevention ofillness and the maintenance of health is its greatest potential benefit, and its safety when used chronically has beenwell established. The future financial burden of medical care could be curbed significantly by the general use oftransfer factor.
SAFETY OF TRANSFER FACTOR
Transfer factor has an excellent safety record, and no adverse side effects have been reported. This has been shown even when TF administered in extreme excess or over several years.49 Infants and the elderly are two groupsmost at risk for infection. The naturally high levels of transfer factor in colostrum clearly indicate its intended useand safety for infants. In particular, oral administration of transfer factor is convenient and easily accepted by allage groups.50 In addition, over 3,000 papers have been written on transfer factor since it was first reported in 1949. Studies on the human use of transfer factor have shown how it can relieve unnecessary suffering simply and safely. For a morecomplete examination of transfer factor and its benefits to human health, interested readers are referred to thebooklet Transfer Factor: Natural Immune Booster. Innate and Adaptive Immunity Working Together
Recent research has significantly advanced our understanding of the interplay between the innate and adaptive immune systems.51 We now know that the innate immune system initiates and improves the slower, but morespecific, acquired immune response.22 The complement system is where the early innate immune reaction and thelater acquired immune reaction merge, providing a continuous immune response.52 Natural Killer (NK) cells arenormally considered part of the innate immune system. Nevertheless, NK cells produce a number of cytokines(messenger molecules) that are potent immune regulators of the adaptive immune response.53 Microbial and Malignant Immune Evasion
Most pathogens invading the human body are actively attacked by the immune system. In order to protect themselves, some pathogens have developed "cloak and dagger" immune evasion techniques. "Cloaking" strategiesinclude a continuous changing of surface antigens in a process called antigenic drift or interfering with antigenpresentation. This strategy makes the infected cell invisible to certain parts of the immune system.54 "Dagger"strategies include the infection and destruction of immune cells themselves, as in the case of the HumanImmunodeficiency Virus (HIV).
Other evasive techniques used by pathogens involve tactics such as shedding antigenic markers. These antigenic markers are the handles the immune system uses to grab onto infected cells. By putting out numerous unattachedhandles, the immune cells have their hands so full that they are unable to effectively attach themselves to realpathogens. Meanwhile, other pathogens disrupt the complement system in order to evade detection. For instance, anelegant pathogenic technique involves the production of imitation complement inhibitory proteins (molecular mimicry) that block complement activation.55 Another evasive technique used by pathogens involves disruption ofcytokine production, which creates a false sense of security in the immune system.56 The evasion of the immune system by cancer cells is an instructive example of how invaders can circumvent immunity. Cancer cells are derived from our own cells. This complicates the immune surveillance process since theylook so much like our normal cells.57 Initially, cells that become transformed into cancer cells retain all of the normalself-markers that define them as our own cells. However, these cancer cells also display markers that should not bepresent on our own cells. These markers indicate that the cell is damaged, and their presence signals the CytotoxicT-lymphocytes (CTLs) to destroy the cell before it has a chance to multiply. But if immune response is slow, forwhatever reason, the cancer cell has a chance to multiply. When the immune system does respond, those cells thatare most susceptible to CTL attack will be selectively killed.
Occasionally a cancer cell will mutate further and yield offspring without self-markers. This situation is critical for two reasons. First, the loss of a self-marker increases the ability of the cancer to metastasize. Second, the CTLscan no longer recognize the cancer cell and destroy it. At this point, the NK cells that target foreign cells take over.
In fact, both natural and elicited antibodies are commonly present in the serum of cancer patients. Unfortunately, theresponses of these antibodies to many cancers are ineffective in stopping tumor growth.58 This weak antibody response however, is often sufficient to launch the complement system. Antibody involvement restricts deposition of the complement-generated iC3b tag to tumor cells, and normal tissuesurrounding the malignant cells should be spared. Activation of the membrane attack complex (MAC) is oftenblocked by inhibitory/regulatory proteins that are normally present on our cells. These same inhibitory/regulatoryproteins are also present on cancer cells. Because of this cancer cells are also able to reject the developing MAC ifits formation is slow. 59 Tumors seem to be able to develop several other immune-escape mechanisms that eitherinactivate specific immune cells or prevent the activation of anti-tumor mechanisms.60 If an infection or cell abnormality is too complex, the inadequately trained immune cells may not be able to develop skills fast enough, causing us to get sick. When this happens, additional outside support may be needed.
Conventionally, we have employed drugs such as antibiotics when we are sick. The function of most drugs is toreplace rather than strengthen the immune system. Oftentimes the toxicity of a drug toward its target microbe orcancer cell will also have a negative effect on other cells or systems of the body.61 On the other hand, the role of asupplement is to strengthen the body from within by working with the body rather than circumventing its naturalfunctions. This approach reduces the risk of toxic side effects. Before recorded history, man used dietarysupplements to improve his health. Most of these supplements were derived from plants containing peculiar healingproperties. Two of the oldest recorded medicinal supplementation codes are the Chinese codex from the Shangdynasty (ca. 1766-1122 BC) and the Indian medical system Ayurveda, first recorded in the seventh century BC. Inancient America, echinacea was used from Texas to Saskatchewan. The whole discipline of ethno-pharmacologydeveloped in order to capture and substantiate the folk medicine of cultures throughout the world.
Many of the oldest and most revered supplements have been found to strengthen the immune system.
Interestingly plants may not be the most ancient source of immune system supplements used by man. The oldestimmunological supplement may in fact be found in the colostrum provided by every mammalian mother who nursesher offspring.
IMMUNOLOGICAL AGENTS FOUND IN COLOSTRUM
Transfer Factor. The first milk of every mammalian mother naturally contains transfer factors that reflect her
rich immunological experience.62 If the baby is allowed to nurse, initial immunity is rapidly established. This isnature's way of quickly educating a naive infant in the hazards of a microbe-infested world.63 On the other hand,infants who are not breast-fed show a greater susceptibility to infections, allergies and childhood cancer.64 The nature of the modern dairy cow is such that she is in intimate microbial contact with her environment and produces far more colostrum—and therefore more transfer factor—than her calf needs. Since transfer factors areuniversally effective regardless of the differences between the species of the donor and the recipient, harvesting theexcess colostrum and isolating the transfer factor provides a commercial source of transfer factor for humanconsumption.
Originally transfer factor preparations were administered by injection.65 However, later studies clearly established that transfer factor is also effective when taken orally. It is obvious that nature intended colostraltransfer factors to be taken orally.
Transfer factor, as an extract of colostrum, is generally recognized as safe (GRAS) and is considered to have a safety profile similar to milk. Although lactose intolerance due to milk ingestion is present to a degree in manypopulations, even persons who are clinically lactose sensitive can tolerate between two and six grams of lactose, as aresult of colonic bacterial degradation of lactose.66 Unlike large-molecule antibodies, transfer factors are quitesmall.67 As stated earlier the small size of transfer factors helps to make them non-allergenic. In fact, it is actuallythe immunoglobulins (antibodies) found in bovine colostrum that are the source of most cow-milk allergies inhumans.68 Antibody (Immunoglobulin) Supplements. Absorption of maternal immunoglobulins ceases after the first 30
hours of life for a human.69 Beyond the first 30 hours of life, no absorption of intact antibodies has been shown inhumans.70 Oral administration of antibodies to adults leads to rapid degradation of the antibodies both due to theacidity of the stomach and the action of intestinal enzymes. This led to the recommendation that both stomach acidand intestinal enzymes be neutralized to obtain maximum benefit from orally administered antibodies.71 Rapid transit and incomplete digestion are the hallmarks of diarrhea. It is in just such a condition that oral ingestion of antibodies is most effective.72 No absorption of the intact antibodies is required since the troublesomeagent is in the intestines.
Antibodies from one species are not effective in other species. No positive systemic effects can be expected after oral administration of foreign antibodies to humans.73 Lactoferrin. Lactoferrin is a protein that binds iron.74 Because of its iron-binding properties, lactoferrin has been
proposed to act as a bacteriostatic agent by withholding iron from iron-requiring bacteria. Lactoferrin is found inhigh concentrations in human colostrum, but the level of lactoferrin in bovine colostrum is very low. Thus,consuming bovine colostrum as a lactoferrin source is not effective.
ZINC AND THYMUS SUPPORT
Zinc. Zinc is an essential element for growth, nervous system function and especially the immune system response.
The relevance of zinc for immune efficiency has been well established.75 Zinc-deficient persons experience
increased susceptibility to a variety of pathogens.76 The regulation of innate immunity, as well as the function and
maturation of lymphocytes and monocytes, is critically dependent on zinc concentration.77
With advancing age, humans undergo a progressive reduction in their zinc leve ls. Studies suggest that the age- related thymic involution (regression) and peripheral, immunological dysfunctions are not intrinsic and irreversible
events but are largely dependent on the altered zinc pool.78 Interestingly, melatonin helps restore zinc balance from
negative to positive values which further demonstrates the interdependence the neuroendocrine, digestive and
immune systems.79 As little as ten milligrams of supplemental zinc improved cell-mediated immune response in an
older population.80 Similarly, only five milligrams of zinc per day reduced morbidity and improved immune
function, as well as growth, in low birth weight, full-term infants.81
Thymulin. Thymulin is a thymus hormone. Diminished levels of thymulin occur in immunodeficiency and
autoimmune diseases. It has been demonstrated that thymulin plays a role in immune and neuroendocrine system
interactions.82 Thymulin has also been shown to reduce inflammatory pain.83 Thymulin is not active by itself.
Thymulin requires an equal amount of zinc for it to be biologically active.84 In one set of tests, the highest degree of
vaccine effectiveness was achieved when a mixture of thymulin and zinc was administered concurrently.85 In the
case of AIDS, levels of total thymulin are not diminished, but the amounts of active thymulin are reduced to nearly
undetectable levels.86 By adding zinc, all of the missing thymulin activity was recovered.
Plasma levels of active thymulin are also reduced in cervical cancer due to low zinc bioavailability. Thus, zinc supplementation may restore impaired central and peripheral immune efficiency in cervical carcinoma.87 A recentexamination of the importance of zinc indicated that it "significantly determines development of diseases".88 AGARICUS BLAZEI (Sen Su Take)
Agaricus blazei is considered by many to be the king of medicinal mushrooms. Reported health benefits of Agaricus blazei span millennia and application of modern scientific methods have validated the traditional use andbenefits of Agaricus blazei. Dr. Fujimiya and his colleagues have studied the effects of Agaricus blazei extracts onsolid tumors. They found that when a solid tumor is injected with Agaricus blazei extracts, the tumor begins toshrink. Most interestingly other tumors present in the host also shrink. Such a distant response is a clear indicationof an immune system reaction.89 Dr. Fujimiya was able to show that the body's natural killer (NK) cells were ableto recognize and actively attack the local and distant tumors.90 Dr. Fujimiya found the cytotoxicity or cell killingactivity of Agaricus blazei was selective for the tumor cells.
Dr. Mizuno, et al. clearly demonstrated that both the helper T-cell (CD4+), and cytotoxic T-cell (CD8+) populations were significantly increased after oral administration of Agaricus blazei extract.91 5-Fluorouracil, acommon anticancer drug, is known to suppress the immune system.92 By including Agaricus blazei polysaccharideextracts in a 5-Fluorouracil drug program, the antitumor effects of 5-Fluorouracil were enhanced. 93 These results,along with the work of Dr. Ito, clearly indicate that Agaricus blazei's antitumor effect occurs through strengtheningthe host's immune system.94 Cordyceps sinensis is a fungus that is highly valued in China as a tonic food and herbal medicine. The use of in Chinese medicine is now centuries old. In ancient China, cordyceps sinensis was used to hasten recovery fromexhaustion, an effect that has recently been scientifically validated. Cordyceps sinensis has been tested in trialsinvolving over two thousand patients. Researchers were unable to establish a toxic dosing level, which shows that itis very safe. The only side effects of chronic ingestion cordyceps sinensis have been an increase in sperm count andtestes weight. A recent exhaustive two-part review of the Chinese and English literature provides a wealth ofhistorical and scientific validation for the safety and benefits of cordyceps sinensis.95 Immune System Effects. Cordyceps sinensis extract greatly increased the very low levels of interferon-gamma,
tumor necrosis factor-alpha, and interleukin-1 in cell cultures of leukemic cells. Cordyceps sinensis also increasedthe production of interleukin 2 and its absorbency by immune cells. Each of these cytokines is associated withincreased antiviral and/or antitumor activity as well as overall immune responsiveness.
A preparation of cordyceps caused significant elevation in the number of helper T-cells and increased the helper to suppressor T-cell ratio. Cordyceps augments the NK cell activity. The importance of these effects should not beunderestimated (For example see previous discussion on natural killer cells).
Antitumor/Cancer. As discussed earlier, tumors use a myriad of methods to escape immune surveillance. Two of
these techniques are down-regulation of self-markers on tumor cell surfaces and reduction of the macrophage
migration toward and engulfment of tumor cells. This latter technique is often dramatically seen in lymphomic
tumors.
The antitumor effect of Cordyceps sinensis is mediated through its immunomodulating action rather than through any direct toxicity toward the cancer cells. Cordyceps sinensis extracts caused an increased appearance ofself-markers, making the host immune surveillance more effective against tumor cells that down-regulated self-markers as a means of immune evasion. Oral administration of cordyceps sinensis also induced an above normallevel of macrophage activity, resulting in reduced lymphoma tumor size and increasing the murine survival rate.
Cordyceps sinensis has been tested against other cancer cell lines as well. Extracts of Cordyceps sinensis increased the median survival time of mice bearing either Ehrlich ascites carcinoma or Meth A fibrosarcoina by over300 percent. Cordyceps sinensis extract, in combination with blood mononuclear cells, inhibited the proliferation ofhuman leukemic U937 cells by 78 to 83 percent. Cancer cells are often immature cells, and maturation of the cancercells diminishes their cancerous characteristics. Examination of the U937 cells after treatment with Cordycepssinensis extract showed that about 50 percent of the leukemic cells had become mature monocytes and macrophages.
Cordyceps sinensis also reduced colony formation of B16 melanoma and helped to maintain NK cell activity in spiteof the presence of the immunosuppressive drug cyclophosphamide, suggesting its potential usefulness in treatingcancer in immunodeficient patients. Helper T cells were also protected from the deleterious effects of the immunosuppressive drug prednisolone acetate. These results further substantiate the potential utility of cordyceps inimmunodeficient or immunosuppressed patients.
Cordyceps sinensis appears to evoke a balanced immune response. In experimental transplants, high doses of cordyceps sinensis (4 g/kg/day) significantly prolonged the survival time of unmatched skin grafts. It has also been rather than independent of this system. The antitumor activity of acemannan in tumors is believed to result frommacrophage activation and the release of antitumor cytokines.114 115 116 Viruses use a variety of mechanisms to avoid destruction by the immune system. One of these mechanisms is the inhibition of T-cells. Pretreatment with acemannan reduced the virus-induced inhibition of T-cells,117 andacemannan therapy was significantly beneficial for cats exhibiting clinical signs of feline immunodeficiency virus(FIV) infection.118 Acemannan is one of only a very few plant-derived, anti-HIV products that have been used in alimited number of patients suffering from AIDS.119 To date, the benefit of acemannan on HIV patient health hasbeen limited in cases of advanced HIV. 120 Acemannan has shown benefit in other areas as well. Acemannan inhibited adherence of the bacteria Pseudomonas aeruginosa to lung cells.121 In addition its use as a vaccine adjuvant was shown to be beneficial eitherin raising or sustaining the immune response.122 Acemannan increased the primary response to the heartwormantigen ten-fold over control levels.123 A combination of melatonin and aloe extract has been reported to arrest,though not reverse, brain carcinoma.124 Also, the safety of acemannan at high dosages has been clearlydemonstrated.125 Further, acemannan does not potentiate HIV-1 or herpes simplex virus type 1 (HSV-1)replication.126 PHYTIC ACID, INOSITOL HEXAPHOSPHATE, OR IP6
Inositol hexaphosphate, also known as phytic acid (IP6), its lower phosphorylated forms (IP 1-5), and inositol are important in regulating vital cellular functions.127 128 129 130 IP6 is found in cereal brans and legumes, and it hasbeen shown to be the agent responsible for much of the anticancer activity of high fiber diets.131 The anticanceraction of IP6 has been demonstrated both in vivo and in vitro against cancers of the liver, breast, prostate, largeintestine and colon. The effectiveness of IP6 against human mammary cancers is independent of the estrogenreceptor status of the cells.
IP6 is rapidly absorbed and metabolized by human malignant cells in vitro. IP6 up-regulates the expression of tumor suppressor genes and also blocks incitement of tumor activator proteins.These discoveries help in part toexplain the decreased tumor aggression and diminished tumor size prompted by IP6.
Olives and Olive Leaf Extracts
OLEUROPEIN, HYDROXYTYROSOL AND ELENOIC ACID
Studies of oleuropein provide a new link between the Mediterranean diet and prevention of coronary heart disease (CHD) and cancer.132 Indeed many of the beneficial effects of the Mediterranean diet may be derived fromoleuropein and its hydrolysis products hydroxytyrosol and elenoic acid.
Oxidatively modified low-density lipoproteins (LDL) contribute to the onset of the atherosclerotic disease.
Natural antioxidants abound in the Mediterranean diet and may contribute to the observed protection from coronaryheart disease (CHD) by retarding the formation of the atherosclerotic plaque. Not only is LDL oxidation inhibitedby oleuropein 133 and hydroxytyrosol134 but also the blood levels of both total and free cholesterol are significantlyreduced.135 The olive tree, Olea europaea, is a potential source of promising antimicrobial agents for treatment of intestinal or respiratory tract infections in man.136 The recent discovery that microbial infection and heart disease arecorrelated137 provides an additional dimension to the protective features of olive and olive leaf extract consumptionin CHD.138 The addition of oleuropein significantly and immediately decreased outgrowth of Bacillus cereus Tspores.139 Low concentrations of oleuropein also delayed the growth of Staphylococcus aureus.140 In additionoleuropein improves the macrophage-mediated response during endotoxin challenge leading to an increased cellularand organismal protection.141 Elenolic acid has been repeatedly demonstrated to exert antiviral activity. Calcium elenolate reduced influenza viral infectivity and was also demonstrated to be both preventive and therapeutic in the case of parinfluenza 3virus.142 More than ten years before HIV was identified, calcium elenolate was shown to inhibit a viral reversetranscriptase enzyme.143 In the case of myxoviruses, Calcium elenolate was found to be as effective as the anti-viraldrug virazole against influenza virus.144 The safety of oral ingestion was demonstrated in rabbits, rats, mice, dogsand humans in both acute and chronic toxicity models.145 Olive and olive leaf extracts provide an array of anti-inflammatory benefits.146 Hydroxytyrosol was the best anti-inflammatory component found in olives.147 Inhibition of inflammation may reduce damage to arterial linings.
Hydroxytyrosol was also highly protective against DNA damage which is involved in the pathology of severalchronic diseases.148 There is growing evidence that reactive oxygen species are involved in the aetiology of fat-related neoplasms such as cancer of the breast and colorectum.149 Hydroxytyrosol is a potent inhibitor of freeradical generation in the feces providing a clear mechanism for prevention of colorectal carcinogenesis.150 The bioavailability and safety of oleuropein and hydroxytyrosol are excellent. Kinetic data demonstrate that hydroxytyrosol can be quantitatively absorbed at the intestinal level with the majority of the absorbed materialexcreted in the urine.151 Neither oleuropein nor hydroxytyrosol were toxic to leukocytes at the concentrationstested.152 Phytosterols are important constituents of healthful diets.153 Legumes, long known for their healthful properties, are one of the best sources of phytosterols.154 Peanuts have also been found to be an excellent source ofphytosterols.155 Beta-sitosterol is the major phytosterol in higher plants. Western processed diets contain only 20-25% of the beta-sitosterol present in vegetarian and Oriental diets.156 Like Vitamin C, humans do not produce anybeta-sitosterol. In nature beta-sistosterol is bound to plant fiber, making it difficult to absorb. Concentrationprocedures break down much of the plant fiber matrix, which should improve the bioavailability of beta-sitosterol.
Phytosterols have been shown to modulate the immune system, inhibit colon cancer development, and normalize cholesterol levels.157 Beta-sistosterol as an immune-modulator is involved in normalizing T-cell function,dampening overactive antibody responses, and rebalancing DHEA:cortisol ratios.158 Proliferation of T-cells,increased secretion of IL-2 and gamma interferon, and increased NK-cell activity are some of the immuneparameters that are enhanced during immune challenge when phytosterols are present.159 Epidemiologic and experimental studies suggest that dietary phytosterols may offer protection from the most common cancers in Western societies, such as colon, breast and prostate cancer.160 Early work demonstrated thatphytosterols including beta sitosterol were protective against chemically induced colon cancers.161 Rao and Janezichave proposed that the interaction of phytosterols with gut microflora protects the colon from toxic metabolites ofcholesterol.162 High intakes of phytosterols also explained most of the gastric and esophageal cancer protection thatresults from high vegetable and fruit intakes.163 Other studies concluded that dietary phytosterols retard the growthand spread of breast cancer cells.164 Mechanistic studies by Awad, et al. are elucidating the mechanisms wherebyphytosterols inhibit prostate cancer cell growth.165 Beta-sitosterol has also been identified as the antimicrobial and antifungal constituent of many medicinal plants.166 When patients suffering from pulmonary tuberculosis added sitosterols to their diet, in addition to anefficacious anti-tuberculosis regimen, the patients' immune parameters and overall quality of life improved.167 Phytosterols including beta-sistosterol have been identified as the active anti-inflammatory principles in cactus and other medicinal plants.168 Beta-sitosterol was found to be nearly as potent as indomethacin in inhibiting earinflammation.169 A decrease in the cortisol: DHEAs ratio may in part explain this diminished inflammation.170 Benign Prostate Hypertrophy (BPH) is a non-cancerous enlargement of the prostate that affects the quality of life for most men as they enter their fifth and subsequent decades of life. In a rigorous and matched study, theefficacy of phytosterols was validated as an effective approach to BPH.171 Beta-sitosterol improves urologicalsymptoms and flow measures in BPH.172 A German multi-center study of 177 BPH patients showed that beta-sitosterol is an effective option in the treatment of BPH.173 These results were supported by the results of a threemonth Japanese study employing a low dose of phytosterol containing 180 mg of sitosterol per day. Significantimprovement in the patients' International Prostate Symptom Scores (IPSS) and their quality-of-life (QOL) scoreswere recorded.174 In a critical review of sitosterol effectiveness in controlling BPH, Lowe and Ku noted that it wassitosterol not its glycoside that has shown the greatest benefit in relieving BPH.175 Four placebo-controlled studiesinvolving 519 men support this conclusion that the non-glucosidic B-sistosterols improve urinary symptoms andflow measures.176 The beneficial effects of beta-sistosterol treatment for BPH were maintained for 18 months.177 Lowering total and especially LDL cholesterol levels is strongly recommended for the prevention of coronary heart disease. Since the 1950's dietary phytosterols have been considered beneficial in regulating cholesterollevels.178 Phytosterols have been shown to lower serum cholesterol in approximately 88% of mildlyhypercholesterolemic subjects.179 Physicians and researchers have stated that the addition of sitosterol and the otherphytosterols to the diet may be the preferred method for controlling hypercholesterolemia in both adults andchildren.180 181 Sitosterol is incorporated into the intestine plasma membranes and significantly decreased theamounts of cholesterol absorbed from the intestinal tract. 182 183 Beta-sitosterol interrupts the recirculation of bile acids and selectively increases LDL receptor expression resulting in a drop in LDL cholesterol levels.184 Beta-sistosterol had inhibitory effects on 3T3-L1 fat cell growth which may play a role in controlling obesity andcholesterol levels.185 Becker and Von Bergmann recommended phytosterols as the "treatment of choice" for severefamilial hypercholesterolemia in childhood.186 Consumption of phytosterols has been shown to be safe and non-toxic.187 Nevertheless Sitosterolemia is a very rare recessive genetic disease.188 These rare individuals born with sitosterolemia are advised to limit their intake ofvirgin oils, fruits and vegetables.
The immune system is an elegant and sophisticated network of cells and molecules that strive constantly to maintain our health and physical integrity against an onslaught of increasingly resistant microbial invaders. Thesemicrobes and our own cancer cells use an array of techniques to evade or subvert our immune responses. Dietarysupplementation discussed in this booklet may help us attain an immunological advantage over invading microbesand invasive cancers.
Zinc is involved in over two hundred critical biochemical functions including immunity. Adequate zinc absorption diminishes with age. Maintenance of the body's zinc levels through dietary supplementation helpsreduce or stop the age related decline in immune function. Reactivation of thymulin by dietary zincsupplementation has been used to recover immune competence in immune compromised individuals.
Rediscovery and scientific validation of the ancient benefits of Sen-su-take, maitake, and shiitake mushrooms as well as cordyceps sinensis provide a valuable basis for the use of these products and their extracts in strengtheningthe immune response. Some of the ingredients of these plants that provide the immunological benefits have beenidentified. Many other minor components may also play signigicant roles in supporting the immune system The beneficial effects of acemannan depend on the presence of the immune system. Beta-glucan has an extensively documented immunological benefit. Recent research has clarified much of the earlier therapeuticconfusion and has led to a rational basis for the effective use of beta-glucan as a biological agent. The combinationof acemannan and beta-glucan appears to provide a greater immunological impact than what occurs when eitheragent is used alone.
The phytosterols are important elements of healthful diets. They help modulate the immune response, inhibit cancer growth, and normalize cholesterol levels. Phytosterols are the active principles in many medicinal plantsexerting antimicrobial, antifungal, and anti-inflammatory activity.
Oleuropein, hydroxytyrosol, and elenoic acid from olive leaf extracts have been shown to be antibacterial, antiviral, as well as being anti-inflammatory. All of these characteristics help protect the body and reduce the strainon the immune system. In addition these natural products are good anti-oxidants and this may in part explain theirability to protect cells from DNA damage that is associated with cancer and other chronic diseases. Inositolhexaphosphate (IP6) appears to act by a different mechanism that results in improved intracellular control ofmalignant cell.
The combination of these agents has demonstrated a synergistic impact on NK cell activity with no measurable toxicity, even at excessively high concentrations. These facts open up the potential for enhanced nutritional supportfor an optimally functioning immune system.
APPENDIX 1. HUMAN AND BOVINE PATHOGENS:
POTENTIAL CROSS REACTIVITY
Human Pathogen or Disease Commonality
Travelers Diarrhea (E.coli) Toxigenic E.coli Bloody diarrhea/hemolytic uremia E.coli 0157:H7 Verotoxic Salmonella thyphimurium,Salmonella typhosa dublin Diarrhea, from food and water Clostridial Infection Clostridia (many species) C. dificil Mycobacterium Infections Mycobacterium species johnei, Crohn's Disease common in Jersey cattle Staphylococcal super infections Staph. aureus Streptococcal Infections S. pyogenes Enterococci (most spp. & VRE) hospital/VRE strains serious Helicobacter pylon (ulcers) Pneumonia Resp. Syncytial Virus Bovine Resp. Sync. Virus Papilloma, Condylomaya Bovine Papilloma Virus Bovine Virus Diarrhea Bovine CMV and IBR Herpes Infections Bovine Rhinotracheitis HIV (Retrovirus) common Bovine Immune Deficiency Rhinoviurs (common cold) Bovine Rhinovirus YEAST, FUNGI and PROTOZOA
Candidiasis
Candida exp. common Calf diarrhea, C. parvum Calf diarrhea, G. lamblia Bvn. Mycopl. Pneumonia REFERENCES1 Lewis R. An Eclectic Look at Infectious Diseases. The Scientist. Aug 21 2000;14(16):1.
2 a) Newsweek Jan 17 2000. b) Commonweal Aug 13 1999. c) 13th Intn'l AIDS Conf. Durban, So. Africa; July2000.
3 Current and evolving therapies for hepatitis C. Moradpour D; Blum HE. Eur J Gastroenterol Hepatol, 1999 Nov,11:11, 1199-202.
4 Pathogenesis, diagnosis and management of hepatitis C. Boyer N; Marcellin P. J Hepatol, 2000, 32:1 Suppl, 98-112.
5 Natural history of hepatitis C and the impact of anti-viral therapy. Boyer N; Marcellin P. Forum (Genova), 2000Jan, 10:1, 4-18.
6 Sulkowski MS. Hepatitis C Virus Infection in HIV-infected Patients. Curr Infect Dis Rep 2001 Oct;3(5):469-4767 Boyer N, Marcellin P. Pathogenesis, diagnosis and management of hepatitis C. J Hepatol 2000;32(1 Suppl):98-112 8 Levy SB. "Antibiotic resistance: an ecological imbalance." Ciba Found Symp. 1997; 207(1-9): 1-9 discussion 9-14.
9 Tauxe RV. "Emerging Foodborne Diseases: An Evolving Public Health Challenge." The National Conference onEmerging Foodborne Pathogens: Implications and Control, March 24-26m 1997, Alexandria, Virginia, USAEmerging Infectious Diseases. 1997; 3(4).
10 Alam R "A brief review of the immune system." Prim Care. 1998; Dec. 25(4):727-38.
11 Roitt I, Brostoff J, Male D. Immunology. Fourth Ed. Moshy, London, 1996.
12 Woods JA, Davis JM, Smith JA, Nieman DC. "Exercise and cellular innate immune function." Med Sci SportsExerc. 1999; 31(1): 57-66. 13 Beilharz MW, McDonald W, Watson MW, Heng J, McGeachie J, Lawson CM. "Low-dose oral type I interferonsreduce early virus replication of murine cytomegalovirus in vivo." J Interferon Cytokine Res, 1997; 17(10): 625-30.
14Medzhitov R, Janeway CA. "Innate immune recognition and control of adaptive immune responses." Jr Seminlmmunol, 1998; 10(5): 351-3.
15 Feizi T. "Carbohydrate recognition systems in innate immunity." Adv Exp Med Biol, 1998; 435: 51-4.
16Medzhitov R, Janeway CA. "An ancient system of host defense." Jr Curr Opin Immunol, 1998; 10(1): 12-5. 17Janeway CA. "The road less traveled by: the role of innate immunity in the adaptive immune response.
Presidential Address to The American Association of Immunologists. Jr. J Immunol, 1998; 161(2): 53 4.
18 Hess C, Steiger JU, Schifferli JA. "Complement and its role in immune response." Schweiz Med Wochenschr.
1998; 128(11): 393-9.
19 Lachmann PJ, Davies A. "Complement and immunity to viruses." Immunological Reviews. 1997; 159: 69-77.
20 Talaro KP, Talaro A. Foundations in Microbiology, 3rd Ed., McGraw-Hill,1999.
21 Lachmann PJ, Davies A. "Complement and immunity to viruses." Immunological Reviews. 1997; 159: 69-77.
22 Talaro KP, Talaro A. "Human Natural Killer cells." Arch Immunol Ther Exp (Warsz). 1998; 46(4): 213-29.
23 Toyama Sorimachi N, Koyasu S. "Regulatory mechanisms of NK cell functions" Nippon Rinsho. 1999; 57(2):304-9.
24 Whiteside TL, Herherman RB. "Human Natural Killer cells in health and disease." Biology and therapeuticpotential. Clin Immunother. 1994; 1(1): 56-66.
25 Page CC, Ben Eliyahu S. "A role for NK cells in greater susceptibility of young rats to metastatic formation." DcvComp Immunol. 1999; 23(1): 87-96.
26 Solana R, Alonso MC. "Natural Killer cells in healthy aging." Peta J Exp Gerontol. 1999; 34(3): 435-43.
27 Solomon GE, Segerstrom SC, Grohr P, Kemeny M, Fahey J. "Shaking up immunity: psychological andimmunologic changes after a natural disaster" (see comments] Psychosom Med. 1997; 59(2): 114-27.
28 De Gucht V, Fischler B, Demanet C. "Immune dysfunction associated with chronic professional stress in nurses."Psychiatry Res. 1999; 85(1): l05-11.
29 Hauser CJ, Joshi P, Jones Q, Zhou X, Livingston DH, Lavery RE. "Suppression of Natural Killer cell activity inpatients with fracture/soft tissue injury. " Arch Surg. 1997; 132(12): 1326-30.
30 Ben Eliyahu S, Page CC, Yirmiya R, Shakhar C. "Evidence that stress and surgical interventions promote tumordevelopment by suppressing Natural Killer cell activity." IntJ Cancer. 1999; 80(6): 880-8.
31 Whiteside TL, Friberg D. "Natural Killer cells and Natural Killer cell activity in chronic fatigue syndrome." Am JMed. 1998; 105:3A, 27S-34S.
32 Albright JW, Albright JF. "Impaired Natural Killer cell function as a consequence of aging." Exp Gerontol, 1998; 33(1-2): 13-25.
33 Montecino-Rodriguez E, Dorshkind K. "Thymocyte development in vitro: implications for studies of ageing andthymic involution." Mech Ageing Dee. 1997; 93(1-3): 47-57.
34 Rose NR. "Thymus function, ageing and autoimmunity." Immunol Lett. 1994; 40(3): 225-30.
35 Lawerence HS. "The cellular transfer of cutaneous hypersensitivity to tuberculin in man." Proc Soc Exp Biol Med1949; 71: 516.
36 Lawrence HS, Borkowsky W. "A new basis for the immunoregulatory activities of transfer factor—an arcanedialect in the language of cells." Cell Immunol. 1983; 82: 102-16.
37 Lawrence HS, Borkowsky W. "Transfer Factor current status and future prospects." Biotherapy 1996, 9(1-3), i-S.
38 Process for obtaining transfer factor from colostrum transfer factor so obtained and use thereof. Wilson GB,Paddock GV. Patent Number US4816563 Patent Date 1989-03-28.
39 Kirkpatrick CH. "Structural Nature and Functions of Transfer-Factors." Annals of The New York Academy ofSciences 1993, 685, 362-368.
40 Pizza C, Visa D, Boucheix CI, Corrado E. "Effect of in vitro produced transfer factor on the immune response ofcancer pateients." Fur J Cancer. 1977; 13: 917-23.
41Fudenberg HH, Pizza C. "Transfer factor 1 993: New frontiers." Progress in Drug Res. 1994; 42: 309-400.
42 Lawrence HS. "The cellular transfer of cutaneous hypersensitivity to tuberculin in man." Proc Soc Lip Biol Med1949; 7l: 516.
43 Kirkpatrick C H, Hamad AR, Morton LC. "Murine Transfer Factors: dose-response relationships and routes ofadministration." Cell Immunol 1995; 164(2): 203-6.
44 Pizza C, Viza D. "Transfer Factor in the Era of AIDS." Biotherapy 1996; 9(1-3): ix-x.
45 Viza D. "Aids and Transfer Factor: Myths, Certainties and Realities." Biotherapy. 1996; 9(1-3): 17-26.
46 Fudenberg HH, Pizza G. Transfer factor 1993: New frontiers. Progress in Drug Res. 1994, 42, 309-400.
47 Pizza C., De Vinci C., Fudenberg HH. "Transfer factor in Malignancy." Progress in Drug Res. 1994; 42: 401-421.
48 "Transfer Factor in the Era of AIDS: The Proceedings of the Xth International Symposium on Transfer Factor,22-24 June 1995, Bologna, Italy." Biotherapy. 1996; 9(1-3): 1-185.
49 Pizza C, De Vinci C, Fornarola V Palareti A, Baricordi 0, Viza D. "In vitro studies during long-term oraladministration of specific Transfer Factor." Biotherapy 1996; 9(1-3): 175-85.
50 Wu S, Zhong X. "Observation of the effect of PSTF oral liquor on the positive tuberculin test reaction." ChungKuo I Hsueh Ko Hsueh Yuan Hsueh Pao 1992; 14(4): 314-6.
51 Carroll MC, Prodeus AP. "Linkages of innate and adaptive immunity." Curr Opin Immunol. 1998; 10(1): 36-40 52 Sakamoto M, Fujisawa Y, Nishioka K. "Physiologic role of the complement system in host defense, disease, andmalnutrition." Nutrition. 1998; 14(4): 391-8.
53 Kos FJ "Regulation of adaptive immunity by Natural Killer cells." Immunol Res, 1998; 17(3): 303-12.
54 Brodsky FM, Lem L, Solache A, Bennett EM. "Human pathogen subversion of antigen presentation." ImmunolRev. 1999; 168: 199-215.
55 Wurzner R. "Evasion of pathogens by avoiding recognition or eradication by complement, in part via molecularmimicry." Mol Immunol. 1999; 36(4-5): 249-60.
56 Scow HF "Pathogen interactions with cytokines and host defense: an overview." Vet Immunol Immunopathol,1998; May, 63(1-2): 139-48.
57 Canss R, Limmer A, Sacher T, Arnold B, Hemmerhing CJ. "Autoaggression and tumor rejection: it takes morethan self-specific T-cell activation." Immunol Rev. 1999; 169: 263-72.
58 Vetvicka V, Thornton BP, Wieman TJ, Ross CD . "Targeting of Natural Killer cells to mammary carcinoma vianaturally occurring tumor cell-bound iC3b and beta-glucan-primed CR3 (CD1Tb/CD1 8)." J Immunol, 1997;159(2): 599-605. See ref 1-4.
59 Vetvicka V, Thornton BP, Wieman TJ, Ross CD . "Targeting of Natural Killer cells to mammary carcinoma vianaturally occurring tumor cell-bound iC3b and beta-glucan-primed CR3 (CD1Tb/CD1 8)." J Immunol. 1997;159(2): 599-605. See ref 6-8.
60 Velders MP, Schreiber H, Kast WM. "Active immunization against cancer cells: impediments and advances."Semin Oncol. 1998; 25(6): 697-706.
61 Zernikow B, Michel F, Fleischhack C, Bode U. "Accidental iatrogenic intoxications by cytotoxic drugs: error analysis and practical preventive strategies." Drug Saf, 1999; 21(1): 57-74.
62 Wilson GB, Paddock CV. "Process for obtaining transfer factor from colostrum transfer factor so obtained anduse thereof." US Patent Number 4816563; Mar. 28, 1989.
63 Fudenberg HH. "Transfer Factor: Past, Present and Future." Ann Rev Pharm Tox 1989; 475-516.
64 Hanson LA. "Breastfeeding Stimulates the Infant Immune System." Science and Medicine. 1997; 2-11.
65 Lawrence HS. "The cellular transfer of cutaneous hypersensitivity to tuberculin in man." Proc Soc Exp Biol Med1949; 71: 516.
66 Hertzler SR, Huynh BC, Savaiano DA. How much lactose is low lactose? J Am Diet Assoc 1996; 96: 243-6.
67 Kirkpatrick CH. "Peptide Sequences That Are Common to Transfer Factors." XIth International Congress onTransfer Factor, 1—4 MAR 1999, Monterrey, Mexico.
68 Bernard H, et al. Int Arch Allergy Immunol, 1998; 115: 235-44. Docena CH, et al. Allergy 1996; 51: 412-6. WalJM. Adv Exp Med Biol 1995; 371B: 879-81. Dean T. EurJ Clin Nutr 1995; 49 ( Suppl 1): S19-25.
69 Vukavic T. Timing of the gut closure. J Pediatr Gastroenterol Nutr 1984 Nov;3(5):700-3.
70 Losonsky GA, Johnson JP, Winkelstein JA, Yolken RH. Oral administration of human serum immunoglobulin inimmunodeficient patients with viral gastroenteritis. A pharmacokinetic and functional analysis. J Clin Invest 1985Dec;76(6):2362-7.
71 Reduction in virus-neutralizing activity of a bovine colostrum immunoglobulin concentrate by gastric acid anddigestive enzymes. Petschow BW, Talbott RD. J Pediatr Gastroenterol Nutr. 1994, 19, 228-35.
72 Sarker SA; Casswall TH; Juneja LR; Hoq E; Hossain I; Fuchs GJ; Hammarström L. Randomized, placebo-controlled, clinical trial of hyperimmunized chicken egg yolk immunoglobulin in children with rotavirus diarrhea. JPediatr Gastroenterol Nutr, 2001 Jan; Vol. 32 (1), pp. 19-25.
73 Carlander D; Kollberg H; Wejåker PE; Larsson A. Peroral immunotherapy with yolk antibodies for theprevention and treatment of enteric infections. Immunol Res, 2000; Vol. 21 (1), pp. 1-6.
74 Lonnerdal B, Iyer S. "Lactoferrin: Molecular Structure and Biological Function." Annual Reviews in Nutrition1995; 15: 93-110.
75 Wellinghausen N, Kirchner H, Rink L. "The immunobiology of zinc." Immunol Today 1997; 18(11): 519-21.
76 Shankar AH, Prasad AS. "Zinc and immune function: the biological basis of altered resistance to infection." Am JClin Nutr 1998; 68:447S-463 S.
77 Wellinghausen N; Rink L. "The significance of zinc for leukocyte biology." J Leukoc Biol, 1998; 64(5): 571-7.
78 Mocchegiani F, Santarelli L, Muzzioli M, Fabris N. "Reversibility of the thymic involution and of age-relatedperipheral immune dysfunctions by zinc supplementation in old mice." IntJ Immunopharmacol. 1995; 17(9): 703-18.
79 Mocchegiani F, Bulian D, Santarelli L, Tibaldi A, Muzzioli M, Lesnikov V, Pierpaoli W, Fabris N. "The zincpoo1 is involved in the immune-reconstituting effect of melatonin in pinealectomized mice." J Pharmacol Fxp Then.
1996; 277:1200-8.
80 Fortes C, Forastiere F, Agabiti N, Fano V, Pacifici R, Virgili F, Piras C, Guidi L, Bartoloni C, Tricerri A, ZuccaroP, Ebrahim S, Perucci CA. "The effect of zinc and vitamin A supplementation on immune response in an olderpopulation." J Am Geriatr Soc 1998; 46: 19-26.
81 Lira P1, Ashworth A, Morris SS. "Effect of zinc supplementation on the morbidity, immune function, and growthof low-birth-weight, full-term infants in northeast Brazil." Am J Clin Nutr 1998; 68: 418S-424S.
82 Safieh-Carabedian B, Kendall MD, Khamashta MA, Hughes C. "Thymulin and its role in immunomodulation." R.
J Autoimmun. 1992; 5(5): 547-55.
83 Safieh-Carabedian B, Jalakhian RH, Saade NE, Haddad JJ, Jabbur SJ, Kanaan SA. "Thymulin reduceshyperalgesia induced by peripheral endotoxin injection in rats and mice." Brain Res. 1996; 717(1-2): 179-83.
84 Coto JA, Hadden EM, Sauro M, Zorn N, Hadden JW. "Interleukin 1 regulates secretion of zinc-thymulin byhuman thymic epithelial cells and its action on T-lymphocyte proliferation and nuclear protein kinase C." Proc NatlAcad Sci USA. 1992; 89(16): 7752-6.
85 Barbour EK, Hamadeh SK, Chanem DA, Haddad JJ, Safieh-Carabedian B. "Humoral and cell-mediatedimmunopotentiation in vaccinated chicken layers by thymic hormones and zinc." Vaccine. 1998; 16(17): 1650-5.
86 Fabris N, Mocchegiani E, Calli M, Irato L, Lazzarin A, Moroni M. "AIDS, zinc deficiency, and thymic hormonefailure." JAMA. 1988 Feb 12; 259(6): 839-40.
87 Mocchegiani F, Ciavattini A, Santarelli L, Tibaldi A, Muzzioli M, Bonazzi P, Ciacconi R, Fabris N, Carzetti CC.
"Role of zinc and alpha2 macroglobulin on thymic endocrine activity and on peripheral immune efficiency (NaturalKiller activity and interleukin 2) in cervical carcinoma." BrJ Cancer 1999; 79: 244-50.
88 Sprietsma JE. "Zinc-contiolled Thl/Th2 switch significantly determines development of diseases." Med-Hypotheses. 1997 Jul; 49(1): 1-14.
89 Fujimiya Y, Suzuki Y, et al. "Tumor-specific cytocidal and immunopotentiating effects of relatively lowmolecular weight products derived from the basidiomycete, Agaricus blazei Murill." Anticancer Res. 1999; 19(1A):113-8.
90 Fujimiya Y, Suzuki Y, et al. "Selective tumoricidal effect of soluble proteoglucan extracted from thebasidiomycete, Agaricus blazei Murill, mediated via natural killer cell activation and apoptosis. Cancer ImmunolImmunother 1998; 46(3): 147-59.
91 Mizuno M, Morimoto M, et al. "Polysaccharides from Agaricus blazei stimulate lymphocyte T-cell subsets inmice." Biosci Biotechnol Biochem 1998; 62(3): 434-7.
92 Graybill JR, Bocanegra R, Najvar LK, Loebenberg D, Luther MF. "Granulocyte colony_stimulating factor andazole antifungal therapy in murine aspergillosis: role of immune suppression." Antimicrob Agents Chemother1998; 42(10):2467-73.
93 Itoh H, Ito H, et al. "Inhibitory action of a (1-->6)-beta-D-glucan-protein complex (F III-2-b) isolated fromAgaricus blazei Murill ("himematsutake") on Meth A fibrosarcoma-bearing mice and its antitumor mechanism." JpnJ Pharmacol 1994; 66(2): 265-71.
94 Ito H, Shimura K, et al. "Antitumor effects of a new polysaccharide-protein complex (ATOM) prepared fromAgaricus blazei (Iwade strain 101) "Himematsutake" and its mechanisms in tumor-bearing mice." Anticancer Res1997; 17(1A): 277-84.
95 Zhu JS, Halpern CM, Jones K. "The scientific rediscovery of an ancient Chinese herbal medicine: Cordycepssinensis: part I." J Altern Complement Med, 1998; 4(3): 289-303. Part II." J Altern Complement Med. 1998; 4(4):429-457.
96 Goldman RC. "Biological Response Modification by b-D-Clucans." Ann Reports Med Chem. 1995; 30: 129-138.
97 Diller IC, Mankowski ZT, Fisher ME. "The effects of yeast polysaccharides on mouse tumors." Cancer Res.
1963, 23:201.
98 Ross CD, Vetvicka V, Yan J, Xia Y, Vetvickova J. "Therapeutic intervention with complement and beta-glucan incancer." Immunopharmacology. 1999, 42(1-3): 61-74.
99 Bowles AP Jr., Perkins F. "Long-term remission of malignant brain tumors after intracranial infection: a report offour cases." Neurosurgery. 1999; Mar. 44(3): 636-42 discussion 642-3.
100 Hoffman OA, Olson EJ, Limper AH. "Fungal beta-glucans modulate macrophage release of tumor necrosisfactor-alpha in response to bacterial lipopolysaccharide." Immunol Lett, 1993; 37(1): 19-25.
101 "Anti-infective effect of poly-beta 1-6-glucotriosyl-beta 1-3-glucopyranose glucan in vivo." Onderdonk AB,Cisneros RU, Hinkson P, Ostroff C. In feet Immun, 1992; 60(4): 1642-7.
102 Dellinger EP Babineau TJ, Bleieher P, Kaiser AB, Seibert GB, Postier RC, Vogel SB, Norman J, Kaufman D,Calandiuk S, Condon RE. "Effect of PGC-glucan on the rate of serious postoperative infection or death observedafter high-risk gastrointestinal operations." Betafectin Gastrointestinal Study Group. Arch Surg. 1999; 134(9) 977-83.
103 Suzuki I; Tanaka H; Kinoshita A; Oikawa S; Osawa M; Yadomae T. "Effect of orally administered beta-glucanon macrophage function in mice. J Immunopharmacol. 1990; 12(6): 675-84.
104 Wasser SP; Weis AL. "Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: amodern perspective." Crit Rev Immunol, 1999; 19(1): 65-96.
105 Jong SC, Birmingham JM. "Medicinal and therapeutic value of the shiitake mushroom." Adv Appl Microbiol,1993; 39: 153-84.0106 Nanha H; Kubo K. "Effect of Maitake D-fraction on cancer prevention." Ann N Y Acad Sci, 1997; 833: 204-7.
107 Estrada A; Yun C-H; Van Kessel A; Li B; Hauta S; Uaarveld B. "Immunoregulatory Activities of Oat ∃-GlucanIn vitro and In vivo." Microbial Immunol 1997; 41(12): 991-998. 108 Zhang U, Tizard JR. "Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fractionfrom Aloe yera gel." Immunopharmacology. 1996; 35(2): 119-28.
109 Roberts DB, Travis EU. "Acemannan-containing wound dressing gel reduces radiation-induced skin reactions inC3H mice." Int J Radiat Oncol Biol Phys. 1995, 32(4): 1047-52.
110 King GK, Yates KM, Greenlee PC, Pierce KR, Ford CR, McAnalley BH, Tizard JR. "The effect of AcemannanImmunostimulant in combination with surgery and radiation therapy on spontaneous canine and felinefibrosarcomas." J Am Anim Hosp Assoc. 1995, 31(5): 439-47.
111 Egger SF, Brown CS, Kelsey US, Yates KM, Rosenberg U, Talmadge JE. "Hematopoietic augmentation by abeta-(1,4)-linked mannan. Cancer Immunol Immunother. 1996, 43(4), 195-205.
112 Womble D, Helderman JH. "The impact of acemannan on the generation and function of cytotoxic T-lymphocytes." lmmunopharmacol Immunotoxicol.1992, 14(1-2): 63-77.
113 Stuart RW, Lefkowitz DL, Lincoln JA, Howard K, Celderman MP, Lefkowitz SS. "Upregulation ofphagocytosis and candidicidal activity of macrophages exposed to the immunostimulant acemannan." Int JImmunopharmacol. 1997; 19(2): 75-82.
114 Harris C, Pierce K, King C, Yates KM, Hall J, Tizard I. "Efficacy of acemannan in treatment of canine andfeline spontaneous neoplasms." Mol Biother. 1991, 3(4), 207-13.
115 Yates KM, Rosenberg U, Harris CK, Bronstad DC, King CK, Biehle CA, Walker B, Ford CR, Hall JE, TizardJR. "Pilot study of the effect of acemannan in cats infected with feline immunodeficiency virus." Vet-Immunol-Immunopathol.1992, 35(1-2), 177-89.
116 Ramamoorthy U, Kemp MC, Tizard JR. "Acemannan, a beta-(1,4)-acetylated mannan, induces nitric oxideproduction in macrophage cell line RAW 264.7." Mol Pharmacol. 1996; 50(4): 878-84.
117 Sharma JM, Karaca K, Pertile T. "Virus-induced immunosuppression in chickens." Poult Sci. 1994, 73(7): 1082-6.
118 Yates KM, Rosenberg U, Harris CK, Bronstad DC, King CK, Biehle CA, Walker B, Ford CR, Hall JE, TizardJR. "Pilot study of the effect of acemannan in cats infected with feline immunodeficiency virus." Vet-Immunol-Immunopathol. 1992, 35(1-2): 177-89.
119 Vlietinck AJ, De-Bruyne T, Apers S, Pieters LA. "Plant-derived leading compounds for chemotherapy of humanimmunodeficiency virus (HIV) infection." Planta Med. 1998, 64(2), 97-109.
120 Montaner JS, Gill J, Singer J, Rahoud I, Arseneau R, McLean BD, Schechter MT, Ruedy J. "Double-blindplacebo-controlled pilot trial of acemannan in advanced human immunodeficiency virus disease." J Acquir ImmuneDefic Syndr Hum Retrovirol. 1996, 12(2): 153-7.
121 Azghani AO, Williams I, Holiday DB, Johnson AR. "A beta-linked mannan inhibits adherence of Pseudomonasaeruginosa to human lung epithelial cells." Glycobiology. 1995; 5(1): 39-44.
122 Chinnah AD, Baig MA, Tizard IR, Kemp MC. "Antigen dependent adjuvant activity of a polydispersed heta-(1,4)-linked acetylated mannan (acemannan)." Vaccine. 1992, 10(8): 551-7.
123 Usinger WR. "A comparison of antibody responses to veterinary vaccine antigens potentiated by differentadjuvants." Vaccine. 1997, 15(17-18), 1902-7.
124 Lissoni P; Ciani U; Zerbini S; Trabattoni P; Rovelli E. "Biotherapy with the pineal immunomodulating hormonemelatonin versus melatonin plus aloe vera in untreatable advanced solid neoplasms." Nat Immun. 1998, 16:1: 27-33.
125 Fogleman RW, et al. "Subchronic oral administration of acemannan in the rat and dog." Vet Hum Toxicol. 1992,34(2): 144-7. "Toxicologic evaluation of injectable acemannan in the mouse, rat and dog." Vet Hum Toxicol. 1992,34(3), 20 1-5.
126 Kahlon JB, Kemp MC, Yawei N, Carpenter RH, Shannon WM, McAnalley BH. "In vitro evaluation of thesynergistic antiviral effects of acemannan in combination with azidothymidine and acyclovir." Mol Biother. 1991,3(4), 214-23.
127 Shamsuddin AM; Vucenik I; Cole KE. "JP6: a novel anti-cancer agent." Life Sci, 1997, 61:4, 343-54.
128 Vucenik I, et al. "IP6 in treatment of liver cancer. Parts I and II. Anticancer Res, l998; 1 8:6A: 4083-90,4091-6.
129 Saied IT; Shamsuddin AM. "Up-regulation of the tumor suppressor gene p53 and WAF1 gene expression by 1P6in HT-29 human colon carcinoma cell line." Anticancer Res, 1998, 18:3A, 1479-84.
130 Huang C; Ma WY; Hecht SS; Dong Z. "Inositol hexaphosphate inhibits cell transformation and activator protein1 activation by targeting phosphatidylinositol-3' kinase." Cancer Res, 1997, 57(14): 28 73-8.
131 Vucenik I; Yang CY; Shamsuddin AM. "Comparison of pure inositol hexaphosphate and high-bran diet in theprevention of DMBA-induced rat mammary carcinogenesis." Nutr Cancer, 1997, 28:1, 7-13.
132 Visioli F, Bellomo G, Galli C "Oleuropein (ester of elenolic acid and 3,4-dihydroxy-phenylethanol(hydroxytyrosol)) Free radical-scavenging properties of olive oil polyphenols." . Biochem Biophys Res Commun 1998; 247(1):60-4.
133 Caruso D, Berra B, et al. "Effect of virgin olive oil phenolic compounds on in vitro oxidation of human lowdensity lipoproteins." Nutr Metab Cardiovasc Dis 1999; 9(3): 102-7.
134 Manna C; Della Ragione F ; Cucciolla V ; Borriello A ; D'Angelo S ; Galletti P ; Zappia V. "Biological effectsof hydroxytyrosol, a polyphenol from olive oil endowed with antioxidant activity." Adv Exp Med Biol 1999, 472(-HD-):115-30.
135 Coni E, Di Benedetto R, et al. "Protective effect of oleuropein, an olive oil biophenol, on low density lipoproteinoxidizability in rabbits." Lipids. 2000; 35(1): 45-54.
136 Bisignano G, Tomaino A, et al. "On the in-vitro antimicrobial activity of oleuropein and hydroxytyrosol." JPharm Pharmacol 1999; 51(8): 971-4.
137 Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W,Willeit J. "Chronic infections and the risk of carotid atherosclerosis: prospective results from a large populationstudy." Circulation 2001 Feb 27;103(8):1064-70.
138 Fleming HP, Walter WM, et al. "Antimicrobial properties of oleuropein and products of its hydrolysis from greenolives." Appl Microbiol 1973; 26(5): 777-82.
139 Tassou CC, Nychas GJ, et al. "Effect of phenolic compounds and oleuropein on the germination of Bacilluscereus T spores." Biotechnol Appl Biochem 1991; 31 (2): 231-7.
140 Tranter HS, Tassou SC, et al. "The effect of the olive phenolic compound, oleuropein, on growth and enterotoxinB production by Staphylococcus aureus." J Appl Bacteriol 1993; 74(3): 253-9.
141 Visioli F, Bellosta S, et al. "Oleuropein, the bitter principle of olives, enhances nitric oxide production by mousemacrophages." Life Sci 1998; 62(6): 541-6.
142 Renis HE "Inactivation of myxoviruses by calcium elenolate." Antimicrob Agents Chemother 1975, 8(2):194-9.
143 Hirschman SZ. "Inactivation of DNA polymerases of murine leukaemia viruses by calcium elenolate." J NatNew Biol 1972, 238(87):277-9.
144 Renis HE. "Influenza virus infection of hamsters. A model for evaluating antiviral drugs." Arch Virol. 1977;54(1-2): 85-93.
145 Renis HE. "In vitro antiviral activity of calcium elenolate." Antimicrob Agents Chemother. 1969; 9(-HD-):167-72.
146 de la Puerta R ; Ruiz Gutierrez V ; Hoult JR. "Inhibition of leukocyte 5-lipoxygenase by phenolics from virginolive oil." Biochem Pharmacol 1999; 57(4):445-9.
147 de la Puerta R ; Ruiz Gutierrez V ; Hoult JR. "Inhibition of leukocyte 5-lipoxygenase by phenolics from virginolive oil." Biochem Pharmacol 1999 , 57(4):445-9.
148 Deiana M ; Aruoma OI ; Bianchi ML ; Spencer JP ; Kaur H ; Halliwell B ; Aeschbach R ; Banni S ; Dessi MA ;Corongiu FP. "Inhibition of peroxynitrite dependent DNA base modification and tyrosine nitration by the extravirgin olive oil-derived antioxidant hydroxytyrosol." Free Radic Biol Med 1999, 26(5-6): 762-9.
149 Owen RW ; Giacosa A ; Hull WE ; Haubner R ; Spiegelhalder B ; Bartsch H. The antioxidant/anticancerpotential of phenolic compounds isolated from olive oil. Eur J Cancer. 2000, 36(10):1235-47.
150 Owen RW ; Giacosa A ; Hull WE ; Haubner R ; Spiegelhalder B ; Bartsch H. "The antioxidant/anticancerpotential of phenolic compounds isolated from olive oil." Eur J Cancer 2000, 36(10):1235-47.
151 Visioli F ; Galli C ; Bornet F ; Mattei A ; Patelli R ; Galli G ; Caruso D. "Olive oil phenolics are dose-dependently absorbed in humans." FEBS Lett 2000, 468(2-3):159-60.
152 de la Puerta R ; Ruiz Gutierrez V ; Hoult JR. "Inhibition of leukocyte 5-lipoxygenase by phenolics from virginolive oil." Biochem Pharmacol. 1999; 57(4):445-9.
153 Steinmetz KA ; Potter JD. "Vegetables, fruit, and cancer prevention: a review." J Am Diet Assoc. 1996;96(10):1027-39.
154 Weihrauch JL, Gardner JM. "Sterol content of foods of plant origin." J Am Diet Assoc 1978; 73: 39-47.
155 Awad AB, Chan KC, Downie AC, Fink CS. "Peanuts as a source of beta-sistosterol, a sterol with anticancerproperties." Nutr Cancer 2000; 36(2):238-41.
156 Messina M, Barnes S. "The role of soy products in reducing risk of cancer." J Natl Cancer Inst 1991, 83(8): 541-6.
157 "Phytosterols." Crit Rev Food Sci Nutr 1999, 39(3): 275-283.
158 Monograph: "Plant sterols and sterolins." Altern Med Rev 2001, 6(2): 203-6.
159 Bouic PJ; Etsebeth S; Liebenberg RW; Albrecht CF; Pegel K; Van Jaarsveld PP. "Beta-Sitosterol and beta-sitosterol glucoside stimulate human peripheral blood lymphocyte proliferation: implications for their use as animmunomodulatory vitamin combination." Int J Immunopharmacol 1996; 18(12): 693-700.
160 Awad AB; Fink CS. "Phytosterols as anticancer dietary components: evidence and mechanism of action." JNutr. 2000; 130(9): 2127-30.
161 Raicht RF; Cohen BI; Fazzini EP; Sarwal AN; Takahashi M. "Protective effect of plant sterols against chemicallyinduced colon tumors in rats." Cancer Res. 1980, 40(2): 403-5.
162 Rao AV; Janezic SA. ‘The role of dietary phytosterols in colon carcinogenesis." Nutr Cancer. 1992; 18(1):43-52.
163 De Stefani E, Boffetta P, Ronco AL, Brennan P, Deneo-Pellegrini H, Carzoglio JC, Mendilaharsu M. "Plantsterols and risk of stomach cancer: a case-control study in Uruguay." Nutr Cancer 2000; 37(2): 140-4. B) DeStefani E, Brennan P, Boffetta P, Ronco AL, Mendilaharsu M, Deneo-Pellegrini H. "Vegetables, fruits, relateddietary antioxidants, and risk of squamous cell carcinoma of the esophagus: a case-control study in Uruguay." NutrCancer 2000; 38(1): 23-9.
164 Awad AB, Downie AC, Fink CS. "Inhibition of growth and stimulation of apoptosis by beta-sistosteroltreatment of MDA-MB-231 human breast cancer cells in culture." Int J Mol Med 2000; 5(5): 541-5.
165 Awad AB; Gan Y; Fink CS. "Mechanistic studies are helping to explain the protective effects of beta-sitosterol,a plant sterol, on growth, protein phosphatase 2A, and phospholipase D in LNCaP cells." Nutr Cancer; 2000; 36(1),74-8.
166 Kiprono PC; Kaberia F; Keriko JM; Karanja JN. "The in vitro anti-fungal and anti-bacterial activities of beta-sitosterol from Senecio lyratus (Asteraceae)." Z Naturforsch [C]. 2000; 55(5-6): 485-8.
167 Donald PR; Lamprecht JH; Freestone M; Albrecht CF; Bouic PJ; Kotze D; van Jaarsveld PP. "A randomisedplacebo-controlled trial of the efficacy of beta-sitosterol and its glucoside as adjuvants in the treatment of pulmonarytuberculosis." Int J Tuberc Lung Dis. 1997;1(6):518-22. COMMENT IN: Int J Tuberc Lung Dis. 1998 Jun; 2(6):522-3.
168 A) Park E, Kahng J, Lee SH, Shin K. "An anti-inflammatory principle from cactus." Fitoterapia 2001; 72(3):288-90. B) Navarro A, De las Heras B, Villar A. "Anti-inflammatory and immunomodulating properties of a sterolfraction from Sideritis foetens Clem." Biol Pharm Bull 2001; 24(5): 470-3.
169 de la Puerta R, Martinez-Dominguez E, Ruiz-Gutierrez V. "Effect of minor components of virgin olive oil ontopical anti-inflammatory assays." Z Naturforsch [C] 2000; 55(9-10): 814-9.
170 Bouic-PJ; Clark-A; Lamprecht-J; Freestone-M; Pool-EJ; Liebenberg-RW; Kotze-D; van-Jaarsveld-PP. "Theeffects of B-sitosterol (BSS) and B-sitosterol glucoside (BSSG) mixture on selected immune parameters ofmarathon runners: inhibition of post marathon immune suppression and inflammation." Int-J-Sports-Med. 1999;20(4): 258-62.
171 Berges RR, Windeler J, Trampisch HJ, Senge T. "Randomised, placebo-controlled, double-blind clinical trial ofbeta-sitosterol in patients with benign prostatic hyperplasia. Beta-sitosterol Study Group." Lancet 1995; 345(8964):1529-32.
172 Wilt TJ, MacDonald R, et al. "Beta-sitosterol for the treatment of benign prostatic hyperplasia: a systematicreview." BJU Int 1999, 83(9): 976-83.
173 Klippel, K F, Hiltl DM, et al. "A multicentric, placebo-controlled, double-blind clinical trial of beta-sit osterol(phytosterol) for the treatment of benign prostatic hyperplasia. German BPH- Phyto Study group." Br J Urol 1997,80(3): 427-32.
174 Kobayashi Y, Sugaya Y, et al. "[Clinical effects of beta-sitosterol (phytosterol) on benign prostatic hyperplasia:preliminary study]." Hinyokika Kiyo 1998, 44(12): 865-8.
175 Lowe FC, Ku JC. "Phytotherapy in treatment of benign prostatic hyperplasia: a critical review." Urology 1996,48(1): 12-20.
176 Wilt T, Ishani A, MacDonald R, Stark G, Mulrow C, Lau J. "Beta-sistosterols for benign prostatic hyperplasia."Cochrane Database Syst Rev 2000; 2: CD001043.
177 Berges RR, Kassen A, Senge T. "Treatment of symptomatic benign prostatic hyperplasia with beta-sistosterol:an 18-month follow-up." BJU Int. 2000 May; 85(7): 842-6.
178 Pollak OJ, Kritchevsky D. "Monographs in Atherosclerosis." New York: Basel (1981)179 Gylling H, Puska P, et al. "Serum sterols during stanol ester feeding in a mildly hypercholesterolemicpopulation." J Lipid Res 1999, 40(4): 593-600.
180 Weizel A; Richter WO. "Drug therapy of severe hypercholesterolemia." Eur J Med Res 1997; 2(6): 265-9.
181 Becker M; Staab D; Von Bergmann K. "Treatment of severe familial hypercholesterolemia in childhood withsitosterol and sitostanol." J Pediatr 1993; 122(2): 292-6.
182 Datsenko, Z. M., G. L. Volkov, et al. "[Lipid composition and activity of certain enzymes in membranes ofintestin al epithelium microvilli in rats with experimental hypercholesterinemia]." Ukr Biokhim Zh 1981; 53(4): 74-9.
183 Nguyen LB, Shefer S, Salen G, Tint GS, Ruiz F, Bullock J. "Mechanisms for cholesterol homeostasis in ratjejunal mucosa: effects of cholesterol, sitosterol, and lovastatin." J Lipid Res 2001; 42(2): 195-200.
184 Sirtori CR; Manzoni C; Lovati MR. "Mechanisms of lipid-lowering agents." Cardiology 1991; 78(3): 226-35.
185 Awad AB, Begdache LA, Fink CS. "Effect of sterols and fatty acids on growth and triglyceride accumulation in3T3-L1 cells." J Nutr Biochem. 2000; 11(3):153-158.
186 Becker M ; Staab D ; Von Bergmann K. "Treatment of severe familial hypercholesterolemia in childhood withsitosterol and sitostanol." J Pediatr 1993, 122(2): 292-6.
187 Ayesh R; Weststrate JA; Drewitt PN; Hepburn PA. "Safety evaluation of phytosterol esters. Part 5. Faecal short-chain fatty acid and microflora content, faecal bacterial enzyme activity and serum female sex hormones in healthynormolipidaemic volunteers consuming a controlled diet either with or without a phytosterol ester-enrichedmargarine." Food Chem Toxicol. 1999 Dec; 37(12): 1127-38.
188 Patel SB ; Salen G ; Hidaka H ; Kwiterovich PO ; Stalenhoef AF ; Miettinen TA ; Grundy SM ; Lee MH ;Rubenstein JS ; Polymeropoulos MH ; Brownstein MJ. "Mapping a gene involved in regulating dietary cholesterolabsorption. The sitosterolemia locus is found at chromosome 2p21." J Clin Invest 1998, 102(5): 1041-4.

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