Mark Corson

By D. Lars. Neumann College. 2018.

It is reasonable to ask whether there is anything ethically suspect about this practice generic 200mg lamictal visa. If cheap 25 mg lamictal, on the other hand 100 mg lamictal fast delivery, the fee is very generous, and it is really intended as a strong incentive for that physician to persuade patients to participate in these trials, then it is prima facie ethically suspect. If he were reluctant to do so, that suggests the practice is potentially ethically corruptive. Sound ethical judgments are always capable of standing the light of day, that is, public scrutiny. There are at least two other construals of that principle that need to be considered in relation to the case of Donald. First, we might take the principle to mean that physicians ought always act in such a way as to maximize the best interests of their patient from the point of view of their best medical judgment. For most medical ethicists today that would be much too broad a warrant for medical paternalism; it would effectively eviscerate the principle of autonomy. The second construal of the principle of beneficence better protects patient autonomy. It says that patients should have the right to determine what they judge to be in their own best interests (within the constraints of good medical practice) from the point of view of their own stable values and life goals. This means that patients do not have to make medical decisions for themselves that are consistent with what a majority of reasonable persons in similar medical circumstances would choose. After all, the argument might go, we allow patients to pursue cosmetic surgery, for the sake of nothing more medically urgent than vanity, even though there are some serious medical risks attached to some of those procedures. This question has a rhetorical ring to it, as if the answer were entirely obvious, but there is room for argument and judgment. To follow up further on that, we would have to specify a number of empirical facts, largely related to Donald’s ability to make decisions that were autonomous enough to warrant moral respect. The fourth ethical principle that has a bearing on our case is the principle of justice. As with the prior principle, there are several different construals we need to consider. Con- sider the case of a physician who has two patients with the same degree of coro- nary artery disease. However, the physician only refers the patient whom he really liked for the surgery. He does not refer the other whom he strongly disliked because the other patient had a history of noncompliance. This will mean that individuals who are financially more well off will have greater access to more expensive experimental therapies. The vast majority of goods and services are distributed in our society on the basis of an individual’s ability to pay. These sorts of consequences are generally not associated with access to other consumer goods, which is why health care might be seen as being morally special. Still, as we shall see below, very few would be prepared to argue that every- one in our society has a moral right to any or all of the health care they might want or need that would offer them any health benefits. Consequently, the most common justice arguments related to health care are that all in our society ought to have assured access to some basic package of health services, perhaps a fairly thick package of health services as proposed by the Clinton Administration in 1993. But even that more generous package would not have guaranteed anyone access to experimental medical therapies of the sort we are discussing. In his case, it would be fair to conclude that this would not be a matter of great moral consequence. In that period of time there is a reasonable chance these thera- peutic interventions will be perfected, which is to say they would become part of the standard medical armamentarium covered by health insurance. In the meantime the quality of his life will continue to be compromised; but he will not have been made worse off by this denial, so this would seem to be a morally tolerable outcome. Edward has some sort of cancer that has not been effectively treated by any current therapies. We have another gene therapy trial that is aimed at attacking the sort of cancer that Edward has. Edward will be dead in a year; he will have no opportunity to wait until the therapy is per- fected and disseminated. Still, he might argue that he has a just claim to at least a fair chance of access to such a trial. The argument might take this form: Gene therapy is not a product of the private effort and investment of some small group of individuals, as would be true with other consumer products. Rather, enormous public investments (tax dollars and university research facilities and training of the researchers them- selves) have made these successes possible. All in our society have contributed to the success of that effort; and consequently, all ought to have at least a fair chance to reap the rewards of that effort. It is unfair that only those who have been espe- cially economically fortunate already should have primary access to such tech- nologies, especially when life itself is at stake. For now it is sufficient to note that not all cases of access to experimental gene therapy are morally alike. There are subtle moral considerations that might tilt our judgment one way or another in a given case. Here is one more example of the sort of considerations that might raise issues of justice. Researchers want a therapeutic outcome for patients in these trials; this is the goal they share with standard medical practice. But they also seek to advance medical knowledge, which needs to be done very systematically. As a result, 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?

The vaccinated birds sero- converted and were protected from subsequent infection cheap 100 mg lamictal with mastercard. Finches: Lesions suggestive of a polyomavirus infec- tion have been described as a cause of acute mortality in two- to three-day-old fledgling order 200mg lamictal mastercard, young adult and mature finches buy lamictal 50mg visa. Many of the fledglings that survived had poor neurologic signs (ataxia, paresis, paralysis, coma). Malnutrition can also cause feather lesions, which might be difficult to evaluate clinically. Organ lesions can be induced by a variety of infectious agents, particularly bacteria. Demonstration of large clear basophilic or ampho- philic intranuclear inclusion bodies is considered suggestive of a polyomavirus infection. The demonstration of waning antibody titers suggests a transient serologic response in exposed birds. A 63,105,106,188,424 swab is used to collect a sample from the cut surface of the liver, negative, clinically normal young. The best demonstrate that there is no correlation between the sample to submit for postmortem confirmation of shedding of polyomavirus in excrement and the titers polyomavirus is a swab of the cut surface of the of neutralizing antibodies. Testing birds twice Several immunostimulants have been anecdotally per year (before and after the breeding season) is rec- suggested as effective in the treatment of birds with ommended to detect intermittent viral shedders. The exact mechanisms involved able problem in the aviary because persistently in- in stopping new cases remains undetermined. Manual removal of any organic debris Depopulation of budgerigar aviaries experiencing followed by the use of appropriate disinfectants is outbreaks followed by restocking with sero-negative required to prevent or contain outbreaks. Sodium birds has been suggested as a method of controlling hypochlorite (5%) is thought to be effective against enzootic infections in this species. With the highly infectious nature of avian polyomavirus, particularly to young Psittaciformes, closed breeding operations that do not allow visitors should be encouraged. A cloacal swab of any bird that is being added to a collection should be analyzed Circoviridae during the quarantine period to determine whether a bird is shedding polyomavirus. A chronic disease characterized by symmetric feather Birds also should be tested for viral shedding during dystrophy and loss, development of beak deformities the post-purchase examination. The disease polyomavirus should be separated from the remainder has been diagnosed in numerous Psittaciforme spe- of the collection, and offspring from these birds should cies in addition to cockatoos. The currently used be raised separately from birds that are not shedding name, coined by Perry in 1981, is “psittacine beak the virus. The applicability of killed and recombinant This disease has been experimentally reproduced in polyomavirus vaccines is being evaluated. The virus hemaggluti- Hooded Parrot Meyer’s Parrot nates erythrocytes from cockatoos and some guinea Malee Ring-necked Parakeet Black Palm Cockatoo pigs (see Figure 32. However, the disease has been documented in several black cockatoos and New World psittacine birds including Amazon parrots, macaws and pionus parrots (Table 32. The incidence of source as a major vehicle for the environmental per- the disease in other commonly maintained captive sistence and natural transmission of the virus. Because vire- toos, Rose-breasted Cockatoos, Little Corellas, Major mia has been shown to occur in infected birds, verti- Mitchell’s Cockatoos, Crimson Rosellas, budgerigars cal transmission would be suspected. One flock of Sulfur-crested Cockatoos decreased suggest a carrier state may exist with vertical or from 120 individuals to 20 over a nine-month period. During the test companion birds are subjected may influence regular period, 26% (8 of 31) of the birds screened were found molting periods or the lack of them. Virus that was recovered Most infected birds survive less than six months to from the crop may have originated from infected cells one year after the onset of clinical signs, though some located in the crop or esophageal epithelium, or may birds have been known to live over ten years in a have been deposited in the crop after swallowing of featherless state. Death usually occurs either from exfoliated epithelium from beak or oral mucosal le- changes induced by secondary bacterial, chlamydial, sions. High concentrations of the virus also can be fungal or other viral agents, or from terminal changes that necessitate euthanasia. The factors that determine whether a bird mounts an immune response or is fatally in- fected could depend on the age at the time of expo- sure, the presence and levels of maternal antibodies, the route of viral exposure and the titer of the infect- ing virus. Neonatal budgerigars infected at less than seven tended from the small intestine to the cloaca. In general, crypto- days of age were found to develop severe disease, sporidiosis occurs only in animals that are immunosuppressed (courtesy of Kenneth Latimer). Following experi- (usually birds with severe beak necrosis or other mental infection, the minimum incubation period is 21 to 25 days. Umbrella is critical for the initial processing and presentation Cockatoo chicks infected at three to eight days of age of viral antigen to the immune system, it can be became depressed by 40 days old and developed pro- postulated that the determining factor in whether an gressive feather dystrophy from 42 to 47 days old. Older birds that develop clinical signs later in life may have been infected at a young age and remained latently infected. This is particularly true in African Grey Parrots, where affected feathers may be red instead of grey. The lane 2 chick (below), shown here with the lane 1 chick, did not develop clinical signs enced by the age of the bird when of disease until 80 days of age. Because all three of these chicks were presumably infected clinical signs first appear. Another observation is the irregular necrosis of the reticular cells in the lympho- cytically depleted spleen, which would suggest per- manent immunosuppression. Experimentally infected Rose-breasted Cockatoo neonates became acutely depressed and anorectic approximately four weeks post-infection. Twenty- four hours later, the feathers appeared to lose their luster and became pale and brittle.

The la t t e r can be deduced only from exp erien ce on many specim ens analyzed in r e p lic a te 50mg lamictal amex. This exp erien ce can be taken from the ensem ble of r e p lic a te s in the current assay batch i f 2 p asses are made through the data: f i r s t to decipher the error stru ctu re purchase lamictal 25 mg mastercard, second to use and d isp la y i t purchase 50mg lamictal with mastercard. However, a sin g le batch may co n ta in too few specim ens to d efin e the error stru ctu re c le a r ly. Each assay batch i s f i r s t analyzed using a stru ctu re of n o n -c o u n tin g -s ta tis tic s errors assumed from exp erien ce on p reviou s b atch es. C oncurrently w ith the a n a ly s is , however, the error stru ctu re of the p resen t batch i s assem bled for fu tu re use and te ste d by ch i-sq u are t e s t s fo r co n sisten cy w ith the assumed stru ctu re. If co n sisten cy i s not observed (showing th at the a n a ly st does not have h is assay system under c o n tr o l), then the stored counting data can be au tom atically reanalyzed a fte r providing the error stru ctu re ju st found during the f i r s t p a ss, or perhaps some w eighted average of the p resen t and p reviou s error stru ctu re. As d efin ed in th ese programs, they are concerned only w ith n o n -c o u n tin g -sta tistic s e r r o r s. In the case o f unknowns, the r e s u lts and errors are fo r a n a ly te co n cen tra tio n. In the case of the ch i-sq u are d a ta , each cum ulation i s again fla g g e d , i f ap p rop riate, according to the same 3 ranges of p as fo r in d iv id u a l specim ens; from the cum ulations, d iscrep a n cies between observed s c a tte r and expected s c a tte r can be d etected w ith g rea ter s e n s it iv it y than from in d iv id u a l specim ens. If past and p resen t s c a tte r are not c o n s is te n t, candidate o u tlie r s must be reexam ined. Presumed o u tlie r s are never discarded a u to m a tica lly ; operator in it ia t iv e is required to accom plish t h is. As a con ven ien ce, the p a r tia lly p rocessed r e s u lts from each batch, or from up to 20 com posited b atch es, can be stored on m agnetic card s. F in a lly , the d r if t (w ith confidence lim its and fla g g in g ) i s c a lc u la te d fo r the com posite of a l l p o o ls. The o f f - lin e programs already d istr ib u te d d if f e r in the fo llo w in g main r e sp ects from those described in S ectio n 3. F ir s t, a n a ly sis fo llo w in g each input of counts extends the time during which the operator must atten d the c a lc u la to r. Second, should i t be d esired to reanalyze a batch of data (fo r exam ple, a fte r d isco v erin g th at the assumed error stru ctu re i s in a p p lica b le to th is b a tch ), a l l the data would have to be keyed in again. In p a r tic u la r , they ad ju st counting tim e on each tube so as to a ch ieve a c o u n tin g -s ta tis tic s error s lig h t ly lower than the n o n -c o u n tin g -s ta tis tic s component of the random error (or la r g e r i f d esired ) [8 ]. T his perm its maximum e f fic ie n c y in the u t iliz a t io n of a v a ila b le counting tim e, and in p r in c ip le reduces the number of counters required to cope w ith the w orkload. Very few were fa m ilia r w ith the philosophy of error a n a ly s is a t the heart of th ese programs. Each lab oratory was provided a c a lc u la to r w ith e s s e n tia l a c c e s s o r ie s , the programs, and d e ta ile d docum entation on the op era tio n and str a te g y o f the programs. In a d d itio n , they were prom ised answers to q u estio n s sent to Vienna, a p o s s ib ilit y of a tr ip to atten d th is Symposium i f they did w e ll, and withdrawal o f th e ir c a lc u la to r s i f they did n o t. This e sta b lis h e s that the whole system can in fa c t be used, and w ithout the requirem ent of a tra in in g cou rse. From the e a r ly ex p erien ce, the most common "abuse” of the system appears to be o u tlie r r e je c tio n. However, th is ex h o rta tio n has been commonly ignored, and o v ero p tim istic hypotheses about co n sisten cy among r e p lic a te s have been perpetuated. The new v ersio n of the programs rev erses the stra teg y : nothing i s discarded u n less the a n a ly st manually in terv en es. Many of the la b o r a to r ie s are now ro u tin ely p rocessin g th e ir data on th is system , but some are apparently n o t. There i s a n atu ral in e r tia in s h iftin g to a new system whose advantages may not be f u lly recognized. Another b a rrier may be the com paratively low speed o f c a lc u la tio n : 1 d u p lica te specimen in about 40-50 seconds. This would reduce enthusiasm in la b o r a to r ie s having la rg e numbers of assays (fo r which the system was however not in ten d ed ). Using the new v ersio n of the programs (S e c tio n 3 ), i t should become p o ssib le to en ter counting data a u to m a tica lly from counters ap p rop riately equipped, or to key in data rap id ly ( i f manual en try i s ch o sen ), w ith a n a ly sis accom plished au tom atically th e r e a fte r. In part t h is sig n ific a n c e can be h ig h lig h ted by improved docum entation, in part i t w ill become more com pelling as fa m ilia r ity w ith the system grows. Im precision p r o f ile s , response error r e la tio n sh ip s, v a ria n ce-ra tio t e s t s , ch i-sq u are t e s t s , and perhaps even con fid en ce lim its are new concepts in most of th ese la b o r a to r ie s. However, as the la b o r a to r ie s come to r e a liz e th a t th ese p ercep tio n s are a v a ila b le a t no c o st to the a n a ly st in time or e f f o r t , and that they allow not only the a n a ly st but a lso h is su p ervisor to d etect anom alies in the assay a t a gla n ce, they should be accorded grea ter a tte n tio n. Although su p rlsin g ly l i t t l e evidence of such support has yet emerged, there i s hope th a t i t w ill do so. N ev erth eless, a d d itio n a l tim e w ill be required to meet the f u l l g o a ls of th is p r o je c t. The introduction of immunoassay to laboratories where environmental changes and limited equipment are likely to limit reliability and precision have emphasized the need for routine evaluation of assay performance. The aim has been to provide both an accurate calibration of the immunoassay response and an assessment of assay error which will allow the assayist to monitor and improve assay performance. As models of immunoassay error are used at all stages of processing they are described in some detail. Analysis of sources of error associated with counting, small perturbation “experimental” errors and assay “drift” is explicitly embraced by the program and is used to screen out untypical assay errors or “outliers”. This is a statistically more reliable estimate of precision than the observed replication for an individual result and when calculated for doses over the working range of the assay yields the precision profile as an important indicator of assay performance.

In contrast to tumor models currently employed 100 mg lamictal with visa, the usual clinical situation requires the treatment of an established tumor generic lamictal 200mg overnight delivery. The major limitation of many trials in gene therapy for the treatment of cancer is the lack of systemic effect of the applied strategy 50 mg lamictal with visa. The only study to date showing a regression of a disseminated intrahepatic tumor used the vascular delivery of retrovirus-producing cells encoding interleukin-2 or -4 by intrasplenic injection, and, thereby demonstrated the efficacy against multilocular but not systemic disease. Alcoholic Liver Disease Innovative approaches in gene therapy allow biomedical research investigations in behavioral-induced diseases. The chronic consumption of alcohol in certain individuals leads to liver diseases resulting in liver failure. To date, therapy for alcoholic liver disease is the cessation of alcohol con- sumption and in the case of end-stage liver disease (liver failure) liver transplanta- tion. Recent studies have provided new insights in the pathogenic mechanisms of alcoholic liver disease. These studies have shown that two mediators are independently important for the induction of liver fibrosis due to ethanol (see Fig. Ethanol con- sumption induces “leaky gut syndrome,” thereby altering intestinal permeability to Gram- negative bacteria colonizing the gut. Endotoxin, derived from the bacteria, increases in the blood and is transported to the liver. Gut-derived endotoxin is found in the liver due to increased permeability of the intestinal lining, the so-called leaky gut syndrome due to alcohol ingestion. These animals are protected from alcoholic liver disease regardless of the level of alcohol consumed. Thus, inhibiting the expression of mediators of pathogensis is an important approach that can be utilized in the use of gene therapy of the liver. While the liver is a challenging organ to deliver therapeutic genes, investigators have developed several methods that make the outlook of gene therapy for liver diseases promising. The ex vivo approach has already been used with some success for the treat- ment of familial hypercholesterolemia in clinical trials but still requires modifica- tions to improve the level of gene expression. Ideally, however, gene therapy can be accomplished to correct genetic defects by in vivo methods. Ideally, a vehicle for in vivo gene therapy for the treatment of liver disease must be liver specific, be able to pass through the endothelial lining to reach the parenchymal hepatocytes while avoiding clearance by Kupffer cells, and be effec- tive in nondividing cells. It is also necessary for the therapeutic gene and the vehicle of delivery to avoid an immune response by the host. Several vehicles are under investigation to be used for the in vivo delivery of therapeutic genes. Investigators are working to manipulate these systems to overcome the disadvantages so that the criteria needed for effective treatment can be met. In addition, gene thera- peutic strategies could theoretically be used to treat acquired diseases such as viral infections of the liver. They should (1) be liver specific, (2) pass through the endothelial lining to reach the parenchymal hepatocytes, (3) avoid clearance by Kupffer cells, (4) be effective in nondividing cells, and (5) avoid an immune response by the host. Therapeutic implications of delivery and expression of foreign genes in hepatocytes. A pilot study of ex vivo gene therapy for homozy- gous familial hypercholesterolaemia. Successful ex vivo gene therapy directed to liver in a patient with familial hypercho- lesterolaemia. Microtubular disruption prolongs the expression of human bilirubin- uridinediphosphoglucuronate-glucuronosyltransferase-1 gene transferred into Gunn rat livers. Expression of human a1- antitrypsin in mouse after in vivo gene transfer to hepatocytes by small liposomes. Specific inhibition of hepatitis C viral gene expression by antisense phosphorothioate oligodeoxynucleotides. Hepatocellular Carcinoma Cao G, Kuriyama S, Du P, Sakamoto T, Kong X, Masui K, Qi Z. Complete regression of estab- lished murine hepatocellular carcinoma by in vivo tumor necrosis factor a gene transfer. Combina- tion suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: Sus- tained antitumor immunity prolongs animal survival. Adenovirus-mediated gene therapy of hepatocellular carcinoma using cancer- specific gene expression. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Noting the demo- graphics of cardiovascular diseases in the population of the United States, nowhere is the medical revolution more likely to impact a significant population of patients, than in the arena of cardiovascular disease. Gene therapy offers the potential to alter, or even reverse, pathobiology at its roots. As researchers learn more about the genetic blueprints of disease, the scope of applicability of this exciting new thera- peutic approach will continue to expand. The therapeutic manipulation of genetic processes has come to embrace both the introduction of functional genetic material into living cells as well as the sequence- specific blockade of certain active genes. As a better understanding of the gene- tic contribution to disease has evolved, so has the breadth of gene manipulation technology. Therapeutic targets have been identified in an effort to improve con- ventional cardiovascular therapies, such as balloon angioplasty or bypass grafting. Entirely novel approaches toward the treatment of acquired diseases, such as the induction of angiogenesis in ischernic tissues, are also being developed. As enthusi- asm grows for these new experimental strategies, it is important for clinicians to be aware of their limitations as well as their strengths, and for careful processes of eval- uation to pave the possible integration of these therapies into routine practice.