While sophisticated laboratory tests are necessary to prove that a speciﬁc liver detoxiﬁcation system is dysfunctional indomethacin 25 mg low cost arthritis medication without ibuprofen, several signs and symptoms can give us a good idea of when the liver’s detoxiﬁcation systems are not functioning well or are overloaded 50 mg indomethacin amex arthritis in collie dogs. In general discount indomethacin 75mg amex rheumatoid arthritis rain, anytime you have a bad reaction to a drug or environmental toxin you can be pretty sure there is a detoxiﬁcation problem. The table below lists symptoms that are directly tied to a particular dysfunction. However, when the excretion of bile is inhibited (a condition called cholestasis), toxins stay in the liver longer. Cholestasis has several causes, including obstruction of the bile ducts and impairment of bile ﬂow within the liver. The most common cause of obstruction of the bile ducts is the presence of gallstones. Currently, it is conservatively estimated that 20 million people in the United States have gallstones. Nearly 20% of women over 40 and 8% of men over 40 are found to have gallstones on biopsy, and approximately 500,000 gallbladders are removed in the United States each year because of gallstones. The prevalence of gallstones in this country has been linked to the high-fat, low-ﬁber diet consumed by the majority of Americans. Impairment of bile ﬂow within the liver can be caused by a variety of agents and conditions (listed below). However, relying on these tests alone to evaluate liver function is not adequate, since laboratory values may remain normal in the initial or subclinical stages of many problems. Among the symptoms people with cellular damage to the liver may complain of are fatigue, general malaise, digestive disturbances, allergies and chemical sensitivities, premenstrual syndrome, and constipation. Causes of Cholestasis • Presence of gallstones • Alcohol • Endotoxins • Hereditary disorders such as Gilbert’s syndrome • Hyperthyroidism or thyroxine supplementation • Viral hepatitis • Pregnancy • Natural and synthetic steroidal hormones Anabolic steroids Estrogens Oral contraceptives • Certain drugs Aminosalicylic acid Chlorothiazide Erythromycin estolate Mepazine Phenylbutazone Sulfadiazine Thiouracil Perhaps the most common cause of cholestasis and impaired liver function is alcohol. In some especially sensitive individuals, as little as 1 ﬂ oz alcohol can produce damage to the liver, in the form of fatty deposits. Diet and Liver Function The ﬁrst step in supporting proper liver function is following the dietary recommendations given in the chapter “A Health-Promoting Diet. If you want to have a healthy liver, there are three things you deﬁnitely want to stay away from: saturated fats, reﬁned sugar, and alcohol. A diet high in saturated fat increases the risk of developing fatty inﬁltration and/or cholestasis. In contrast, a diet rich in dietary fiber, particularly soluble fiber, promotes increased bile secretion. Special foods rich in factors that help protect the liver from damage and improve liver function include high-sulfur foods such as garlic, legumes, onions, and eggs; good sources of soluble ﬁber, such as pears, oat bran, apples, and legumes; vegetables in the brassica family, especially broccoli, brussels sprouts, and cabbage; artichokes, beets, carrots, and dandelion; and many herbs and spices such as turmeric, cinnamon, and licorice. Drink alcohol in moderation (no more than two glasses of wine or beer or 2 ﬂ oz hard liquor per day for men, half that for women), and avoid alcohol altogether if you suffer from impaired liver function. Alcohol overloads detoxiﬁcation processes and can lead to liver damage and immune suppression. Follow the Recommendations for Nutritional Supplementation The recommendations given in the chapter “Supplementary Measures” for nutritional supplementation are quite useful in promoting detoxiﬁcation. A high-potency multiple vitamin and mineral supplement is a must in trying to deal with all the toxic chemicals we are constantly exposed to. Antioxidant vitamins such as vitamin C, beta-carotene, and vitamin E are obviously quite important in protecting the liver from damage as well as helping in detoxiﬁcation mechanisms, but even simple nutrients such as B vitamins, calcium, and trace minerals are critical in the elimination of heavy metals and other toxic compounds from the body. Low ﬂuid consumption in general and low water consumption in particular make it difﬁcult for the body to eliminate toxins. As a result, low water consumption increases the risk for cancer and many other diseases. Drinking enough water is another basic axiom for good health that you’ve probably heard a thousand times. But it’s true: you need to drink at least six to eight glasses of water (48 to 64 ﬂ oz) each day. Don’t wait until you’re thirsty; schedule regular water breaks throughout the day instead. Special Nutritional Factors Choline, betaine, methionine,44,45,46 vitamin B , folic acid, and vitamin B are important. These 6 12 nutrients are lipotropic agents, compounds that promote the ﬂow of fat and bile to and from the liver. In essence, they have a decongesting effect on the liver and promote improved liver function and fat metabolism. Formulas containing lipotropic agents are very useful in enhancing detoxiﬁcation reactions and other liver functions. Nutrition-oriented physicians recommend lipotropic formulas for a wide variety of conditions, including a number of liver disorders such as hepatitis, cirrhosis, and chemical-induced liver disease. In taking a lipotropic formula, the important thing is to take enough of the formula to provide a daily dose of 1,000 mg choline and 1,000 mg methionine and/or cysteine. Plant-Based Medicines and Liver Function There is a long list of plants that exert beneﬁcial effects on liver function.
It was for this reason that experiments with activated nylon were discontinued discount 50 mg indomethacin with visa degenerative arthritis in dogs symptoms, despite excellent results published for immobilized enzymes using a nylon support [4—6] indomethacin 50mg cheap healing arthritis in the knee. Teflon discs Teflon is one of the most stable and inert polymers known and it must be activated before it can be used for covalent binding studies buy 50mg indomethacin visa arthritis shots. This activation is somewhat vigorous and is performed using metallic sodium in either liquid ammonia at —70°C or aqueous ammonia, (S. The Teflon discs are added to the reaction mixture as soon as the sodium has finished reacting. The reaction between the Teflon and sodium/ammonia is probably a self- perpetuating free radical one in which the solvated electrons from the sodium play an important role. The reaction of interest is the replacement of fluoride by amide anions, giving rise to “aminated Teflon”. The amino-Teflon can be used to couple antibodies and proteins covalently using either the carbodiimide reaction, or further activation with pentan-1,5-dial. The second activation of the amino-Teflon is by reaction with pentan-1,5- dial followed by washing and addition of protein. A third possibility of introducing another functional group, namely a thiol, is by reacting the amino-Teflon with N-acetyl homocysteine thiolactone at pH 9. Table I shows the application of thyroglobulin-Teflon discs in an immuno- radiometric-style test. Up until now the Teflon discs have proved best for larger molecules such as antibodies, and proteins such as thyroglobulin. Efforts to immobilize insulin for use in an insulin antibody test have not given very encouraging results, at least not yet. Although the assays here described are with Teflon discs, it is feasible to couple antibodies to Teflon “sticks” and develop “dip and measure” immunoassays. The concept of an “optimal method” for adsorptive technique cannot be supported, the adsorption being dependant upon several factors, not to mention the support used. The somewhat unexpected result that at least three antisera were adsorbed best when dissolved in distilled water is probably not as bizarre as it may first appear. Here there is no “compulsion” of the antiserum to bind at a given pH and ionic strength. This is especially true where potentially interfering or inhibitory substances are present in the sample to be measured. In other words it appears that the methods which are to replace radioimmunoassays will be more dependent upon solid phases, either with immobilized antibodies or antigens. The detection system chosen for the assay will play an important but secondary role. Wood indicated that distilled water had been found the best medium for coating solid phase. The difference observed between the polystyrene balls and polystyrene tubes tested was attributable to their surface finish. The binding capacity of Ab immobilized on solid phase was recognized to depend both on the surface density and on the nature of the binding to the solid phase. This agent could increase several-fold the effective coating of antisera on inorganic calcium phosphate gel, polypropylene, polystyrene and other solids. The activation was thought to be due to simple coating rather than to a chemical reaction. A speaker warned, however, that glutaraldehyde was an extremely variable reagent and that individual batches might prove very different in behaviour. Il s’agit d’un ensemble tube-objet particulièrement avantageux dans les techniques à double site anticorps. Le polymère synthétique utilisé pour sa fabrication offre la possibilité de fixer les anticorps aussi bien par adsorption ("coating") que par couplage covalent [21. Les anticorps ont été obtenus par 3 techniques différentes: - précipitation des yglobulines au sulfate de sodium (18 % + 12 %). Milieu réactionnel - Standards Les réactions se déroulent en milieu tampon à pH 7,2 contenant du sérum animal. Pour les dosages à double site nous avons suivi le protocole décrit plus haut (Figure 1). Quels que soient les résultats considérés le revêtement le plus adapté à nos dosages est une adsorption de yglobulines de chèvre après traitement à pH 2,5. Par contre en incuba tions successives, le phénomène est pratiquement inexistant. Validation du dosage Les tests classiques de dilution et recouvrement fonction nent correctement tant sur sérum que sur liquide amniotique.
To date we cannot predict with certainty that Parkinson’s patients who are ideal candidates for a transplant will beneﬁt from this grafting procedure proven 25mg indomethacin cortisone injections for arthritis in back. One of the primary problems with transplanting neurons into the lab animal and human brain has been the issue of poor graft survival cheap indomethacin 75mg online exercises to prevent arthritis in fingers. In humans only about 5% of the fetal dopamine neurons survive using the current transplantation protocols discount 50mg indomethacin fast delivery arthritis knee exercises nhs. This raises the issue of just how representative are the animal models of human neurological disorders. Although fetal neurons have shown the greatest potential in terms of graft survival and clinical efﬁcacy for Parkinson’s, there are serious concerns associated with the use of human fetal neurons, namely tissue availability, quality control, and ethics. To circumvent some aspects of these problems, research has examined neural xenografts for Parkinson’s and the use of stem or neuronal cells grown in culture. It is now possible to isolate subpopulations of stem or neuronal progenitor cells from the developing or adult nervous system, expand the cells in culture, and then use the cells for transplanta- tion or as vehicles for gene delivery to selected sites of the nervous system. These cells survive in vitro in media enriched with growth factors and with passage express a neuronal phenotype. A major advantage of using progenitor cells for transplan- tation is that they have not been transformed or immortalized and exist naturally in the brain. Continued collaborative efforts between the basic and the clinical research sectors using stem or progenitor cells for ex vivo transgene delivery will be critical to the progression of effective therapy for Parkinson’s and other neu- rodegenerative conditions. As previously described, a variety of non-neuronal primary cells and cell lines have been used largely as a way to deliver an active substance that promotes survival or growth of neurons. Research centered on cell replacement strategies now focus predominantly on the use of neural stem cells. Stem Cells in the Adult Brain Until just a few years ago, it was generally assumed and believed that the adult brain was incapable of generating new neurons. Research on a number of fronts has estab- lished that the adult mammalian brain contains stem cells that can give rise to the full spectrum of neurons and glial cells. In particular, the subventricular zone, an important layer that forms during development and persists into adulthood retains the capacity to generate both neurons and glial cells (Fig. Stem cells by strict deﬁnition over the lifetime of the animal must be able to proliferate, show self-renewal, produce progeny with multilineage characteristics, and divide when injured. Progenitor cells refer to cells with a more restricted potential than stem cells, and precursor cells refer to cells within a given developmental pathway. The presence of neural stem cells in the adult brain has established the possibility for using the mature brain as a source of precursor cells for transplantation and helps to establish new therapy directions for neurological injury and disease. In fact, as our understanding of stem cell neurobiology grows, it may be possible to control the proliferation and migration of such cells into areas of the nervous system affected by the diseases discussed in this chapter. The notion of self-repair in the brain is now visible at the basic research level. The potential growth factors governing the commitment and differentiation of the neuronal lineage are indicated. More- over, these newly generated neurons had also made connections to their appropri- ate target. Multipotent stem cell proliferation and differentiation can be regulated by neu- rotrophic factors. When growth factors are added in sequence to neural stem cells, they regulate whether the cells will acquire neuronal or glial characteristics. One sector of gene therapy research focuses on a neural-stem-cell-based strat- egy. With the capability of differentiating along multiple cell lineages, stem cells may be very effective for the delivery of therapeutic gene prod- ucts throughout the brain or spinal cord. The enzyme deﬁciency in this mouse model causes lysosomal accumulations of undegraded glycosominoglycans in the brain and other tissues that results in fatal degenerative changes. Similar therapeutic paradigms are also being evaluated for other inherited neurogenetic diseases that are characterized by an absence of discrete gene products. Engineered cells and progenitors are also being grafted into mouse models of hexosaminadase deﬁciencies causing Tay-Sachs and Sandhoff disease. Clones of stem cells or prog- enitor cells are used extensively to study aspects of differentiation along neuronal and glial lineages. These types of progenitor cell lines have been useful in the iden- tiﬁcation of molecules and neurotrophic factors that initiate and modulate differ- entiation at speciﬁc developmental time points. The myc family of protooncogenes consist of a number of well-characterized members including c-myc,N-myc, and L-myc. This retrovirus induces a number of carcinomas in addition to the leukemic disorder myelocytomatosis (myc) in birds and can transform primary cells in tissue culture. The transformation of cells from the developing nervous system with a retrovirus expressing v-myc have revealed extraordinary characteristics. In culture, progenitor cells immortalized with the v-myc oncogene divide continuously.
But they also seek to advance medical knowledge 75 mg indomethacin otc early onset arthritis in back, which needs to be done very systematically purchase indomethacin 25mg online arthritis neck pain treatment. As a result cheap indomethacin 25 mg with mastercard arthritis pain pills for dogs, it will often be the case that patients will be denied access to one of these clinical trials if, in addition to their primary medical problem for which they are seeking entry to the trial, they have a serious co-morbid condition that could poten- tially compromise the quality of the clinical data they are seeking to gain. Is there any ethical justiﬁcation for denying such patients an equal chance to be a participant in such a trial, especially if we have in mind an Edward-like patient as opposed to a Donald-like patient? To make certain that the ethical issue here is clear we need to emphasize that no matter what the co-morbid condition is that we imagine, those patients have just as good a chance of a successful therapeutic outcome in that trial as any other patient in the trial. That is, these researchers will claim that they are seeking to bring about the greatest good for the greatest number. More precisely, if the clinical data that is gathered in these trials is “tainted” through unknown effects associated with these co-morbid conditions, then there may be some tragic bad outcomes that come about when the results of these trials become part of standard clinical practice. So we have to imagine that there might be at some point in the future a large pool of potential patients who might be seriously harmed as a result of an incorrect clinical conclusion that we draw now. Researchers claim that they are morally obligated to do all in their power to prevent such possible future disasters. The whole point of both moral and political rights is to protect individuals against the encroachments of large and powerful social organizations, either in the private or public sector. Individuals may not have their deep moral rights violated for the sake of advancing some larger social good. The moral basis for this judgment is the Kantian principle of respect for persons we discussed earlier. Individuals cannot be simply used as mere things to advance even noble social goals without their free consent. A standard example in the ethics literature is the skid row bum who drunkenly stumbles in the street to be hit by a car. His head injuries are such that if surgery is done immediately he will likely be restored to something close to his former state of health. However, if surgery is delayed several hours, his con- dition will worsen and he will end up brain dead. His organs can then be used to save the lives of ﬁve other upstanding citizens who very much want to live but who otherwise would die of organ failure. We would certainly judge that any transplant surgeon who took advantage of a situation like this would be doing something grossly unethical. Someone might argue in response that there is a major disanalogy between this case and our Edward-like gene therapy case (where Edward is denied access to a clinical trial because of some co-morbid condition), namely, that our skid row bum is negligently harmed by delaying the surgery that will certainly beneﬁt him. Edward is not treated negligently; he is simply being denied the opportunity to beneﬁt from access to the trial. Edward will be denied access to the clinical trial because of a co-morbid condi- tion on the grounds that the quality of the clinical data might be corrupted by his participation. But the harm that we would hope to avoid there is potential, remote, maybe best described as “speculative” since we cannot assign any speciﬁc proba- bility to the likelihood of that occurring. Even from a utilitarian point of view, the argument goes, should not such devastating harm to an individual be given greater moral weight than remote and speculative possibilities of harm to possible individuals far in the future? We do sometimes make such judgments in medicine, invoking what is referred to as the rule of rescue analogy. Are these clinical trials for gene therapy one of those circumstances in which this rule is justiﬁably invoked? We move now to our third issue that arises in connection with our principle of justice. To set the stage for that issue we need to make explicit an assumption that has been silently operative in our two prior justice problems. Speciﬁcally, we have assumed that these clinical gene therapy trials are more likely than not going to have a therapeutic outcome. That assumption probably reﬂects characteristic American optimism about our scientiﬁc endeavors. But strictly speaking we are not entitled to that assumption, especially in the earliest stages of clinical trials. And, in some circumstances, it might be more appropriate to have a serious concern about poten- tial harms. That in fact is what motivated the early ethical discussions about medical experimentation. There were the Nazi medical experiments, which are best seen as being maliciously motivated. But then there were also the Tuskegee experiments that involved African-American men who were allowed to go untreated for their syphilis, even after we had penicillin that would have cured them. The argument given for non- treatment was that we were in the middle of a medical experiment that we had to allow to run its course for the sake of scientiﬁc knowledge.