We are very excited to now be able to offer Dinamune® for aquaculture species. Independent research has shown that Dinamune® has a significant impact on survival and growth of confined shrimp and fish growing operations when challenged by pathogenic viruses and bacteria.

Here are some very important and very interesting conclusions from recently
published scientific literature which corroborate the efficacy of Dinamune®

The ongoing excerpts have been extracted from some of the more prominent independent research. They are suggestive of the mechanism whereby Dinamune is able to fortify the immune system and therefore make evident the efficacy of Dinamune®:

• All multi-cellular animals that have been investigated so far have mononuclear phagocytes analogous to macrophages in higher animals and man. Carbohydrates that stimulate human and murine (mice) macrophages are known to elicit defense reactions in lower animals.
• Among the strongest carbohydrate stimulants (studied) were several beta 1, 3 configurations.
• In a wide range of invertebrates and especially crustaceans, beta glucans activate prophenoloxicase (proPO) system. The proPRO system represents the terminal component of a complex cascade of enzymes which function in the non-self recognition and hosts defense, causing increases in activations such as bactericidosis, phagocytosis, and encapsulation. In crustaceans, beta glucans activate hemolymph clotting.
• When compared by quantitive analysis, the immuno-stimulative effects of PMA (phorbol 12-myristate 13-acetate, Sigma) and Zymosan (a crude protein-carbohydrate yeast extracted from Saccharomyces Cervisiae, Sigma), and beta glucans, the beta 1,3 glucans extracted from S.Cervisiae (similar but less pure than Dinamune®) produced the strongest immunostimulation effect of the three. 5-Optimum protective effect was shown against Vibrio vulnificus in shrimp at a level of 5-10 ppt. The effectiveness of immersion treatments was demonstrated against Vibrio vulnificus in shrimp. Results showed that PO phennoloxidase activity could be induced with beta glucans. Enhanced growth was shown in shrimp immersed in beta glucan.

Dinamune® is a highly purified form of combined food and feed grade active ingredients. There are no intermediate carriers to add additional labor, packaging, process and freight costs. With Dinamune® you get only what you pay for at the highest possible concentration of active materials consistent with safe handling guidelines. Dinamune® is the trade name for the combination of a highly purified yeast extract chemically known as beta 1-3 -D- glucan . The active ingredients found in Dinamune® are Generally Recognized As Safe (category GRAS according to the FDA), therefore not considered drugs. Dinamune® has no toxicity or adverse side effects. Dinamune® is a polysaccharide molecule with a glucose construction. Glucose is a simple saccharide cell that transforms to energy as Adeno Triphosphate (ATP) and can be then stored in muscle, liver and other tissues in its modified glycogen form. The beta 1-3-D- genesis of Dinamune® is different from energy storing glucose containing polysaccharides because the structural links between the glucose units are different. More specifically, it is the beta 1-3-linkage which makes Dinamune® highly effective in eliciting an immune cascade reaction.

BASIS FOR DINAMUNE'S DEVELOPMENTAL HISTORY
The 1,3-D-glucan found in Dinamune® has a long trajectory of scientific research and scrutiny and a copious reference list. The initial research originated in the 1940's when Pilfer and his colleagues described what amounted to be a crude yeast cell wall preparation. Even at this early developmental stage these researchers came to the conclusion that they had been able to stimulate nonspecific immunity responses by utilizing the yeast extract.

It was unknown at the time which element of this composition, containing a relatively crude mixture of proteins, lipids and polysaccharides, was responsible for the activation of the immune response. The answer came later in the 60's when the late Dr. Nicholas DiLuzio at Tulane University experimented with several glucans and discovered that beta 1-3 - D - glucan configuration isolated from the cell wall of yeast was primarily responsible for the enhanced immune response that had been previously observed by other researchers.

HOW DOES DINAMUNE® WORK ?
It was In the late 1980's that Dr. Joyce Czop, at Harvard University, described the mode of action of Beta-Glucans in stimulating the immune system: He surmises the information by stating that there are highly specialized receptors on the surface of certain of the larger immune system cells called macrophages that can be activated also by beta 1-3-D-glucan. Since the macrophage is evidently unable to distinguish the 1-3 Beta Glucan from a primary pathogen at specific receptor sites it triggers and activates a "cascade" of immune events in much the same manner as if an actual pathogenic challenge existed.

BUILDING AN IMMUNE RESERVE BANK
The resultant increase in immunological "Reserves" is tantamount to building and having available large cash reserves in a bank account to be used as needed.

The term macrophage is derived from the suffix "phage" which means to eat and "macro" which is indicative of it's size. They are any of the large phagocytic cells of the reticuloendothelial system. There are various types of specialized macrophages. For instance the histiocyte is a relatively inactive, immobile macrophage found in normal connective tissue. It is Also called a fixed macrophage. There are fascinating discoveries continually made regarding some of the beneficial tangential effects of macrophages. One such is that it is now known that a protein produced by macrophages in the presence of an endotoxin has shown experimentally to be capable of attacking and destroying cancerous tumors. This has tremendous implications in the field of cancer research. Another is that a substance known as interleukin-1 (IL-1), belonging to a group of protein substances, is released by macrophages and other cells in response to challenge, and are able to induce the production of interleukin-2 by helper T cells and thereby stimulate the inflammatory response of the immune system.

It can be therefore safely surmised from the above that as the largest phagocytes in the immune system, macrophages, play a fundamental and very important role in the initiation and continuity of the immune response. Humans and higher animals as well as primitive invertebrates such as Hydra, have macrophages as part of their immune system. As such all the preceding can benefit from the stimulatory properties found in Dinamune®. In order to function immunologically, the macrophages must pass through a state of activation. This involves certain morphological changes in the macrophage.

DINAMUNE® CATALYZES METABOLIC CHANGES IN THE MACROPHAGE
Macrophage activation produces a whole sequence of metabolic changes. These metabolic changes result in the production of a series of cytokines which act as internal regulators of the immune system. Activation can be initiated by a variety of different stimuli, such as endotoxin, bacteria, fungus, viruses or chemicals. However, Dinamune® is the only such activator which has been shown not only to be completely safe but also has been shown to be one of the most potent stimulatory agents of the immune response.

DINAMUNE® ADJUVANT ABILITIES
By definition an adjuvant is an immunological agent that increases the antigenic response. [From Latin adiuvans, adjuvant, present participle of adiuvare, to help.], or A pharmacological agent added to a drug to increase or aid its effect. When Dinamune® was added to antibiotic regime in animals challenged with different bacteria (Staphylococcus Aureus, Klebsiella Pneumonia, Escherichia Coil and others) and viral (Herpes virus) pathogens, a reduced amount of antibiotics or antivirals was needed to cope with the infection. The former clearly demonstrates Dinamune's adjuvant properties. Dinamune ® also has an antifungal effect, shown in an experiments with Candida Albicans. Such a broad anti-infective spectrum of Dinamune® can be explained only by the fact that the immunostimulation produced by this unique material is non-specific.

CLINICAL EVIDENCE IN MAMMALIAN ORGANISMS
The activated macrophage is a veritable powerhouse in terms of activity. Not only can a macrophage recognize pathogenic and tumor cells nonspecifically as cited earlier, as well as removing foreign debris, but it can produce a number of essential cytokines that are able to stimulate the immune system in general and boost the amount of bone marrow produced in higher animals. Individuals, human or animal, by reason of age or other factors, such as chronic infection or inadequate nutrition, may over a period of time develop a diminished immune system.

PROBLEMS RELATED TO A DIMINISHED IMMUNE SYSTEM
The following problems are frequently induced by a diminished immune response:

• Reduced cicatrization capacity (decreased fibrin response).
• Reduced bone marrow proliferation with resulting lowered white cell counts and resulting anemia.
• Increased incidents of all kinds of viral, fungal, and bacterial infection. The frequency of impairment of the immune system in the course of an individuals life is thought to be increasingly and surprisingly high. Not only environmental influences like UV radiation, electro-magnetic fields, food preservatives and antibiotics can cause temporary immunosuppression, but also stress and heavy physical exercise have these negative effects. Under these influences the number of macrophages available are reduced and unable to participate in the immune cascade which causes even deeper immunosuppression. Dinamune® has been proven to both stimulate and activate macrophage cells which will counter these negative effects. Recent experiments completed at Baylor College of Medicine in the laboratory of Professor Phil Wyde also prove the oral effectiveness of Dinamune® to stimulate nonspecific immunity. Peritoneal macrophages doubled their phagocytotic activity in mice fed with Dinamune®.

The systematic effect of oral application of Dinamune® is comparable to that achieved with injections, which makes this material a unique and very valuable oral immunostimulant. Because the mechanism of Dinamune® macrophage activation appears to be the same between mammals, fish or shrimp, it is not surprising that current studies are showing similar effectiveness in aquaculture species as studies in mammals.

CLINICAL EVIDENCE IN AQUACULTURE ANIMALS
Dinamune® is effective in all mammals as it is in birds, fish, and many invertebrates. Independent studies performed at the National Taiwan University have shown that it successfully protects shrimp against vibriosis. Other Studies are showing protection against, yersiniosis and furunculosis in shrimp when it is added to the feed or when they are immersed in Dinamune® suspension. Initial studies feeding shrimp with Dinamune® challenged with the Taura Virus have shown promise by producing increased viability rates in excess of 90% in some of the study replicates. However, variability in uncontrolled conditions between replications in this first challenge study also produced variable survival data between replications that nullified statistical significance. The fact that some challenged Dinamune® protected replication's survival was so much higher than the unprotected Taura Virus challenged controls, could indicate that immune system enhancement had taken place. Additional and more controlled studies are underway to define effectiveness and to refine the incorporation and presentation techniques for Dinamune's addition to shrimp and fish feeds.