Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-08-14
2004-02-10
Navarro, Mark (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007310, C435S007330, C435S007340, C435S007350, C435S007370, C436S501000
Reexamination Certificate
active
06689569
ABSTRACT:
BACKGROUND OF THE INVENTION
It is increasingly evident that human diseases are most often related to lifestyle and should in theory be preventable. The stress of modem life, our reduced physical activity, and our consumption of manipulated and processed foods, and of chemicals—including pharmaceuticals—all contribute to our decreasing resistance to disease. Much evidence supports the fact that our genes, adapted during millions of years to the lifestyle of our prehistoric ancestors, tolerate poorly the dramatic changes in lifestyle that have occurred, especially in food habits during the past 100 years. Changes in food habits in Western countries that no doubt constitute stresses to the human body and that may predispose to inflammatory, infectious, ulcerative, degenerative, and neoplastic diseases include the following: the consumption of 100 lb. refined sugar per individual per year; the 10-fold increase in sodium consumption; the fourfold increase in consumption of saturated fat; the doubled consumption of cholesterol; a much reduced consumption of vegetable fibres, and of minerals such as potassium, magnesium, calcium, and chromium; and a considerable reduction in consumption of omega-3 fats, membrane lipids, vitamins, and antioxidants. In severe disease, important food ingredients, such as arginine, glutamine, taurine, nucleic acids, vitamins, and antioxidants, such as glutathione, are often not supplied in large enough quantities.
Perhaps, even more important than the decrease in these food ingredients is the fact that prehistoric food contained several thousand times more bacteria, mainly the so called probiotic bacteria. Prehistoric methods of food preservation were either drying or, more commonly, storing in holes dug into the ground, where the food became naturally fermented. This is how Stone Age man learned to produce most of our still common fermented foods, such as beer, wine, green olives, and sauerkraut. Our modern lifestyle has dramatically reduced the availability of foods produced by natural fermentation. After the early identification of microbes, bacteria were regarded mainly as a source of disease, and unwanted in commercially manufactured food. Furthermore, the desire of the food industry to prolong shelf life promoted alternative production methods, such as the use of enzymes instead of live bacteria. With extensive hygiene measures practiced during delivery and in childcare, children in Western societies may have difficulty developing a satisfactory protective indigenous gut flora. It is not known, but suspected, that this could be connected to the increasing incidence of allergies and infections seen among Western children. A series of studies were published about an ethnic group in New Guinea with a dramatically different diet to that of people in the Western world. This diet contained no processed foods like butter, margarine, lard, oils, refined sugar, or alcohol. Instead, the group's diet was rich in fibre, water, vitamins, minerals, and omega-3 fats, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Despite the fact that about 80% of the population smokes and has a heavy consumption of saturated fat from coconut, cerebrocardiovascular diseases are virtually absent and the incidence of diabetes and cancer is very low.
The Gastrointestinal Tract—the Port of Infectious Diseases
The condition and function of the gastrointestinal (GI) tract are essential to our well-being. After the respiratory tract, the GI tract constitutes the second largest body surface area, described to be somewhere between 250 and 400 m
2
, or comparable in size to a tennis court. During a normal lifetime, 60 tons of food pass through this canal, which is important for well being, but also constitutes an enormous threat to the integrity of the digestive tract and the whole body. It is not surprising, therefore, that this organ is often affected by inflammatory diseases and cancer. The continuous challenges to the GI surfaces might be why most of the surface cells have a rapid turnover; most are replaced after three to four days in man and sometimes earlier in animals. Furthermore, the surface is protected by large quantities of important secretions, from saliva in the oral cavity to colonic secretion in the large bowel. These secretions contain factors of great importance for the lubrication of the mucosa and for functions of the GI tract, but also hundreds of ingredients of importance for intraluminal microbial defense. The secretory functions are extremely sensitive to foreign chemicals. About 50% of the 2000 pharmaceutical drugs registered in Sweden have reported GI side effects, for example, mouth dryness, nausea, vomiting, diarrhea, and constipation. It is hoped that future medicine will be more restrictive in the use of pharmaceuticals in general and will use drugs with as few side effects as possible.
Stress and Nutritional and Xenobiotic Influences of the GI Tract
Stress is known to affect the composition of the intestinal preventive flora. Infants fed on artificial infant formulas have, in contrast to breastfed ones, a very low degree of colonization with lactobacilli and bifidobacteria, but high counts in enterococci, coliforms, and clostridia. This may relate to excessive hygiene measures during delivery in Western countries, which prevent transfer of anaerobic microflora from mother to infant. It is also known that cosmonauts on return to Earth have lost their lactobacillus flora, especially
L. planatarum
, which is partly replaced by a higher intestinal content of PPMs, changes attributed to stress and poor eating. Also, xenobiotics (an exogenous agent, such as an environmental chemical not usually present in the body) in the diet can affect the contents of intestinal microflora.
In a recent observation, it was proposed that ulcerative colitis is induced by xenobiotic metabolites, damaging the colonic epithelial barrier and exposing the mucosal immune system to luminal contents. It is possible to account for all of these observations by proposing that ulcerative colitis is caused by a toxic metabolite of a xenobiotic which is excreted in bile and activated during its passage through the colon. Intermittent exposure to the parent compound would be a feature of the environment, possibly part of the diet, in areas where the disease is more common.
The genetic influence could be explained by inherited differences in the capacity of the hepatic enzymes responsible for its metabolism, resulting in decreased elimination of the parent compound by its usual pathway and increased transformation into the reactive metabolite. The most likely candidate enzymes are members of the cytochrome P450 superfamily of mixed-function oxidases, although genetic polymorphisms of other enzymes involved in xenobiotic metabolism have been described. Induction by smoking or inhibition by estrogen of the P450 enzymes involved in alternative metabolic pathways would affect the proportion of the parent compound transformed into the toxic metabolite. Reactive metabolites produced by this system are commonly coupled to an endogenous conjugate, such as glucuronic acid, before excretion into bile.
Bacteria in the gut have enzymes which can act on luminal substrates. In particular, bacterial &bgr;-glucuronidase and sulphatase are capable of hydrolysing the products of hepatic conjugation. If the xenobiotic metabolite were to be slowly reactivated by intestinal bacteria, its luminal concentration would rise with passage down the colon. Once the concentration became toxic, the colonic epithelial barrier would be breached, allowing the mucosal immune system to react to luminal contents distal to that point. In susceptible individuals, the biliary epithelium could also be damaged by the toxic metabolite, allowing presentation of biliary antigens to surrounding lymphocytes by cells carrying appropriate HLA molecules, thereby initiating an inflammatory response in the biliary tree.
Assessment of Intestinal Integrity
Imbalance of gut mucosa permeability is the origin of the intestina
Immunosciences Lab., Inc.
Navarro Mark
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