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By Y. Brontobb. Central Bible College. 2018.

With reperfusion discount 1 mg arimidex with mastercard, reactive oxygen molecules and microvascular events 1 mg arimidex for sale, such as hemolytic–uremic are released that then moderate further injury. These diseases are usually clinically appar- Damage to the renal tubular epithelial cells ultimately ent. The process of healing is char- tion, such as seen with nonsteroidal anti-inflammatory acterized by tubular cell dedifferentiation and pro- agents and several types of antibiotics (Table 6. This risk is a result of Acyclovir several factors including the extensive use of nephro- Foscarnet toxic medications, veno-occlusive disease in associa- Cidofovir tion with hepatorenal syndrome, the high incidence of sepsis, and tumor lysis syndrome [33, 40, 61]. With such patients, it is important to note preoperative renal function, Calcineurin inhibitors intraoperative details such as ischemic time, periods Vasoconstrictor pressor medications of severe hypotension, bypass pump time, as well as Nephrotoxins causing acute interstitial nephritis any perioperative hypoperfusion event. A there is no evidence, however, suggesting benefit or negative balance may suggest effective volume deple- harm to this practice vs. If available, serial weights are invaluable for the assess- ment of fluid balance. Goldstein converting enzyme inhibitors, or calcineurin inhibi- suggest tubular dysfunction or could point toward tors). Serum levels of pertinent medications must be an osmotic diuresis with resultant hypovolemia. Proteinuria may be a nonspecific marker of values will clarify the degree of acute dysfunction. The fractional excretion of ease and hepatorenal syndrome may have remarkable sodium is calculated by the following formula: ascites, abdominal vascular anomalies, or even jaun- (Urine sodium × serum creatinine/serum sodium × dice. The fractional excretion of urea is similarly calcu- Second, the physical examination allows some lated by concomitant measurements of urinary and determination of the extent that the effects of either serum urea nitrogen and creatinine. Alternatively, the patient with sepsis and used, the fractional excretion of sodium may not be severe capillary leak syndrome may have severe total reliable. The fractional excretion of urea is, however, body volume overload and edema, but decreased much less affected by diuretic use [35]. Correlating changes in nine, urea nitrogen, electrolytes, sodium, potassium, oxygen requirement and ventilatory support with bicarbonate or total carbon dioxide, phosphorous, cal- changes in fluid balance may help determine the extent cium, glucose, albumin, hemoglobin, and platelets. Conversely, hypernatremia with Amphotericin B and aminoglycoside neph- may also be seen in the setting of severe dehydration, rotoxicity. Increased examination of renal vessels is a useful adjunct if vas- fluid overload is also associated with increased mortal- cular perfusion anomalies are suspected, although more ity in children receiving continuous renal replacement specialized imaging such as computed tomography therapy [26, 29]. Frequent calculation of fluid balance or magnetic resonance imaging may be needed to and reassessment of fluid provision should be part make a more definitive diagnosis. Avoidance of further renal injury is also a necessary focus of care but difficult to achieve in the critically ill patient with multiple organ dysfunction. Use of nonnephrotoxic medication as alter- tions, avoiding or minimizing further renal injury, natives to more traditional nephrotoxic medication and providing appropriate nutrition to allow recovery should be considered. This decision will be based upon specific and renal dose dopamine (ranging from 1 to 5μg kg−1 patient characteristics as well as local expertise with min−1) for critically ill oliguric patients is prevalent specific dialysis techniques. Prevention dopamine infusion has also been associated with other of fluid overload is extremely important, but often potentially adverse physiologic effects in critically ill difficult to achieve. One nesiritide may have favorable renal hemodynamic suggested method to assess fluid overload status is effects and can increase urine output after cardiac Chapter 6 Acute Kidney Injury: General Aspects 95 Table 6. Infants demonstrate even Management of fluids higher mortality rates when compared with older Restriction of fluids if fluid overloaded (provide children [56, 62]. They tend to be medically complex patients with such as growth factors [42], erythropoeitin [51], and multiple organ dysfunction. Kidney Int 71: 1028–1035 ferrin protects against renal ischemia-reperfusion injury. Andreoli S (2004) Clinical evaluation and manage- Transplantation 77: 669–675 ment. A comparison of hemofiltration and peritoneal in patients undergoing cardiothoracic surgery. Crit Care els, fluid therapy and information technology needs: the Med 32: 1771–1776 Second International Consensus Conference of the Acute 27. Pediatr Nephrol 19: 91–95 replacement therapy: A report of the prospective pediatric 41. Pediatrics 118: sated heart failure: Evidence for a pediatric cardiorenal e786–e791 syndrome? Arch predictors of death in pediatric patients with multiple organ Pediatr Adolesc Med 156: 893–900 system failure. Crit Care Med 22: 1025–1031 Pharmacotherapy 7 in the Critically Ill Child with Acute Kidney Injury M. However, recent stud- depends on the interplay of two entities, namely phar- ies suggest that the kidney plays more than just the role macokinetics and pharmacodynamics. Finally, the kidney plays a major role in deter- of specific drug-metabolizing enzymes [82].

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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 1 mg arimidex with visa. Researchers claim that they are morally obligated to do all in their power to prevent such possible future disasters quality 1 mg arimidex. 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. This would be another clear case where invoking utilitarian considerations would not be ethically justified. The more serious point is that in the case of Tuskegee, and in the case of Willowbrook (retarded children and orphans), and in the case of the Jewish Hospital in New York (old senile patients), socially disfavored groups were used as experimental material for risky medical interven- tions. That is, these were individuals who were captives of institutions who were not in a position to give free and informed consent to assume the risks associated with these medical experiments. There was an imposition of risks and burdens on these individuals for the sake of benefits that would go to other individuals. The motivations of the medical researchers may not have been ethically corrupt, as in the Nazi case, but the outcomes were nevertheless strongly morally objectionable. These are concerns that we need to be mindful of in the case of gene therapy as well. Appropriate Candidates for Gene Therapy We now turn to another dimension of ethics issues in gene therapy, namely, who the candidates are for therapy. We start with competent adults, and we begin by noting that we are using the term competence in its accepted meaning in medical ethics as opposed to law. If an individual is generally capable of managing the tasks of daily life for himself, then he is competent.

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Exhaustion may be manifested as a partial or total collapse of a body function or specific organ buy arimidex 1mg amex. Two of the major causes of exhaustion are loss of potassium ions and depletion of adrenal glucocorticoid hormones like cortisone discount 1mg arimidex amex. Adrenal glucocorticoid depletion diminishes glucose control, leading to hypoglycemia. Prolonged stress places a tremendous load not just on the adrenals but also on many other organ systems, especially the heart, blood vessels, and immune system, and is associated with many common diseases. Diseases Strongly Linked to Stress Angina Asthma Autoimmune disease Cancer Cardiovascular disease Common cold Depression Diabetes (type 2) Headaches Hypertension Immune suppression Irritable bowel syndrome Menstrual irregularities Premenstrual tension syndrome Rheumatoid arthritis Ulcerative colitis Ulcers Stress: A Healthy View The father of modern stress research was Hans Selye. Having spent many years studying this subject, Selye developed valuable insights into the role of stress in disease. It is not the stressor that determines the response; instead it is the individual’s internal reaction, which then triggers the response. What one person may experience as stress, the next person may view entirely differently. Selye perhaps summarized his view best in the following passage from his book The Stress of Life:2 No one can live without experiencing some degree of stress all the time. You may think that only serious disease or intensive physical or mental injury can cause stress. Crossing a busy intersection, exposure to a draft, or even sheer joy are enough to activate the body’s stress mechanisms to some extent. Stress is not even necessarily bad for you; it is also the spice of life, for any emotion, any activity causes stress. The same stress which makes one person sick can be an invigorating experience for another. The Stress Scale Evaluating the impact of stress on a person’s health status requires a complete clinical assessment (review of systems, medical history, physical exam, sleep history, etc. Many people who are stressed out may not be able to identify exactly what is causing them to feel stressed. Typical presenting symptoms are insomnia, depression, fatigue, headache, upset stomach, digestive disturbances, and irritability. One useful tool to assess the role that stress may play is the social readjustment rating scale developed by Holmes and Rahe (see below). Various life-changing events are rated according to their potential to cause disease. Notice that even events commonly viewed as positive, such as an outstanding personal achievement, carry stress. If a person is under a great deal of immediate stress or has endured a fair amount of stress for a few months or longer, it is appropriate to assess adrenal dysfunction more accurately with laboratory methods. The standard interpretation of the social readjustment rating scale is that a total of 200 or more units in one year is considered to be predictive of a high likelihood of experiencing a serious disease. However, rather than using the scale solely to predict the likelihood of serious disease, anyone can use it to determine his or her level of stressor exposure, because everyone reacts differently to stressful events. Salivary cortisol levels are reproducible, comparable to plasma levels, and easy to assess. Generally, an initially overactive acute stress response results in elevated cortisol levels, but chronic stress, insomnia, or depression may blunt this effect. Adrenal exhaustion is a common side effect of continual high stress as well as of steroid drugs such as prednisone, used in the treatment of allergic or inflammatory diseases. Therapeutic Considerations Whether you are aware of it or not, you have developed a pattern for coping with stress. Unfortunately, most people have found patterns and methods that ultimately do not support good health. Negative coping patterns must be identified and replaced with positive ways of coping. Try to identify any negative or destructive coping patterns listed below and replace those patterns with more positive measures for dealing with stress. Stress management can be substantially improved by focusing on the following six equally important areas: • Techniques to calm the mind, promote parasympathetic tone, and promote a positive mental attitude • Lifestyle factors • Exercise • A healthful diet designed to nourish the body and support physiological processes • Dietary and botanical supplements designed to support the body as a whole, but especially the adrenal glands • Supervised stress management program Negative Coping Patterns Dependence on chemicals: legal and illicit drugs, alcohol, smoking Overeating Too much television Emotional outbursts Feelings of helplessness Overspending Excessive behavior Calming the Mind and Body Learning to calm the mind and body is extremely important in relieving stress. The goal of relaxation techniques is to produce a physiological response known as a relaxation response—a response that is exactly opposite to the stress response that reflects activation of the parasympathetic nervous system. Although an individual may relax by simply sleeping, watching television, or reading a book, relaxation techniques are designed specifically to produce the relaxation response. The term relaxation response was coined by Harvard professor and cardiologist Herbert Benson in the early 1970s to describe a physiological response that he found in people who meditate.

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They can establish interactive teams of scientists and physicians who are able to conduct the complex clinical trials needed to find the best matches between the expanding universe of therapeutic options and the genetic constitution of an individual patient cheap arimidex 1 mg fast delivery. Successfully transformed cells are selected and returned to the patient where they home to the original location of removed cells or tissue discount arimidex 1mg free shipping. A gene vector construct, suitable for the delivery of genes to the targeted cell or tissue, is generated. The therapeutic gene is incorporated onto the construct and the recombinant vector is delivered to the patient by any of a number of methods. The method of choice should be previously shown to provide the best level of transfection with minimal side effect. Currently, somatic gene therapy, which targets nongermline cells (nonegg and nonsperm cells), is consistent with the extension of biomedical science and medical therapy in which treatment does not go beyond the individual. In altering the genetic material of somatic cells, gene therapy may correct the specific disease pathophysiology. Cancer Cancer is a genetic disease that is expressed at the cellular level (see Chapter 10). The generation of neoplasia is a multistage process driven by inheritance and rela- tively frequent somatic mutation of cellular genes. Germline mutations result in all cells of an individual becoming at risk for cancer development and thus are not suitable for somatic cell gene therapy. But in both somatic and germline mutations, clonal selection of variant cells results in a population of cells with increasingly aggressive growth properties. In individuals with only somatic gene mutations, the insertion of a gene (such as a tumor suppressor gene) would alter the phenotype of a malignant cell only if the mutation is not dominant. Additionally, the level of corrective cellular therapy (pos- sibly as high as 100% correction of all tumor cells) would need to be determined as well as the issue of gene therapy in distal metastasis. Thus, substantial biological obstacles remain to be overcome in the application of gene therapy in certain forms of cancer. These include: gene transfer of cytokines or other immune mediators to augment host immune responses, the genetic modification of neoplastic cells to promote immunogenicity, the treatment of localized cancers with genes encoding viral or bacterial enzymes that convert prodrugs into toxic metabolites, or the trans- fer of genes that provide enhanced resistance to conventional chemotherapy (see Chapter 10). Infectious Diseases Chronic infectious diseases are suitable targets for gene therapy. Gene therapy strategies for diseases caused by rapidly proliferating infectious pathogens include intracellular immu- nization and polynucleotide vaccines. Gene-therapy-induced vaccination for these pathogens may represent an effective strategy by acting classically to “prime” innate immunity prior to exposure to the pathogen. Intracellular immunization seeks to transform cells into cells that are refactory to infection. Genetic Vaccination Polynucleotide or genetic vaccination seeks to attenuate the host’s immune response, thus having both prophylatic and therapeutic potential. New and more effec- tive vaccines are urgently needed in the United States and throughout the world to prevent infectious diseases. Immune responses have been generated against viral, bacterial, parasitic, allergy-inducing immunogens, and tumor-specific antigens. The plasmid is grown in bacteria (Escherichia coli), purified and injected or blasted into target tissues of the recipient. Most vaccination vectors also contain an intron, which enhances expression of genes in mammalian cells. Because the vaccine contains only a single viral protein, it is called a “subunit” vaccine, in contrast to vaccines comprised of attenuated live viruses or inactivated whole viruses, which contain many viral proteins. Thus, it is hoped that they will be effective not only as preventive modalities but also as therapeutic vaccines. Therapeutic vaccines would be given to infected patients to stimulate immune clearance of established pathogens. Organ Transplantation and Cellular Engineering Organ Transplantation Organ and tissue transplantation are accepted treat- ments for end-stage organ damage. Current survival rates for major organ trans- plantation procedures range from 70 to 95% survival for 1 year to 30 to 75% for 5-year survival. These results indicate that the transplantation procedure itself is no longer a survival issue but that posttransplantation complications reduce long- term survival. Posttransplantation complications include acute and chronic allograft, rejection, infection, and the side effects of immunosuppresive treatments. Gene therapy approaches have been suggested as novel methods to control posttrans- plantation complications at the molecular level. For in vivo gene therapy, adenovirus vectors (see Chapter 4) have been used to obtain efficient gene transfer to the lung and heart in a posttransplantation setting. The efficacy of such procedures show the feasibility of genetic modification of the graft to reduce posttransplantation rejection, such as chronic graft vascular disease in cardiac allograft rejection, or other physiological processes. The graft rejection process could be modified by inserting specific genes of immunosuppressive mole- cules or by transfecting genes of antisense molecules to block expression of an important mediator of graft rejection. In addition to immune-mediated graft rejection, graft func- tion is also important.

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Slaughter and Brown (123) demonstrated positive colposcopic findings in 87% of female complainants of nonconsensual penile penetration within the previous 48 h order arimidex 1 mg on-line, whereas gross 92 Rogers and Newton visualization has historically identified positive genital findings in only 10– 40% of cases (37–39 purchase 1 mg arimidex otc,124,125). Second, with the attachment of a still or video camera, the colposcope allows for a truly contemporaneous, permanent video/photographic record of the genital/anal findings without resorting to simultaneous dictation, which has the potential to distress the complainant. If a video is used, it will docu- ment the entire genital examination and will show any dynamic changes, such as reflex anal dilatation. If appropriate, the medical findings can be demon- strated to the complainant and carer; some teenagers have apparently appreci- ated the opportunity to have any fears of genital disfigurement allayed by the use of this equipment. Finally, if a remote monitor is used, the whole examination can be viewed by another doctor for corroboration or teaching purposes without additional parties having to be present during the intimate examination. Obviously, it is important that in all cases the colposcopic evidence be interpreted in the context of the limited information that is currently available regarding colposcopic assessments after consensual sexual acts (90,126,127). Toluidine Blue Toluidine blue stains nuclei and has been used on the posterior fourchette to identify lacerations of the keratinized squamous epithelium that were not apparent on gross visualization (128,129). Use of toluidine blue increased the detection rate of posterior fourchette lacerations from 4 to 58% in adult (older than 19 years) complainants of nonconsensual vaginal intercourse, from 4 to 28% in sexually abused adolescents (11–18 years old), and from 16. The same frequency of posterior fourchette lacerations has been identi- fied by use of the stain in adolescents after consensual penile penetration and nonconsensual sexual acts (129). In contrast, adult complainants of nonconsensual vaginal intercourse and sexually abused children had signifi- cantly more lacerations demonstrable by toluidine blue staining than control groups (130), although such staining does not identify lacerations that cannot be detected using a colposcope (123). Therefore, if a colposcope is not avail- able, toluidine blue may be an adjunct to the genital assessment of prepubertal and adult complainants of vaginal penetration (129,130). Furthermore, some centers use the stain during colposcopy to provide a clear pictorial presenta- tion of the injuries for later presentation to juries (123). Toluidine blue (1%) is then painted on the posterior fourchette, using Sexual Assualt Examination 93 a swab, before any instrumentation. After a few seconds, the residual stain is removed with lubricating jelly and gauze (128). The time parameters within which the use of toluidine blue is beneficial in highlighting injuries have not been identified. Injuries Little information is available regarding the incidence and type of geni- tal injuries that result from consensual sexual acts involving the female geni- talia. Although penile–vaginal penetration is the most frequent sexual act performed by heterosexual couples, anecdotal reports from doctors who regu- larly conduct nonforensic assessments of the female genitalia (general prac- titioners, gynecologists, or genitourinary physicians) suggest that injuries resultant from sexual activity are rarely identified. However, this may be explained by the nature of routine assessments, which are usually limited to naked-eye inspection or because of the rapid and complete resolution of minor injuries (90). On the other hand, there are reports describing genital injuries in complainants of sexual assault, although, unfortunately, few have matched the findings with the specific complaint or the subsequent outcome in court. To date, no case-control study has compared the genital findings in complainants of sexual assault with those in a sexually active control popu- lation. External Genitalia For penile penetration of the vagina to occur, the penis must first pass between the labia minora and through the hymenal opening. The apposition of the penis and the posterior fourchette in the majority of sexual positions means that this area may be stretched, rubbed, or receive blunt trauma as vaginal penetration is achieved. Lacerations, abrasions, or bruises at the posterior fourchette have all been described after consensual sexual activity, although in all these cases, the examinations were enhanced by the use of toluidine blue or a colposcope (90,128,129). Wilson (131) has also described macroscopi- cally visible hematomata of the labia with consensual sexual activity. Among 311 postpubertal females (age range 11–85 years) who made a “valid” (defined as “police investigation corroborated the victim’s history and the victim did not recant”) complaint of sexual assault, 200 had colposcopically detected injuries at one or more of the following sites on the external genita- lia: posterior fourchette, labia minora, hymen, and fossa navicularis (90). Although all categories of injuries (“tears,” bruises, abrasions, redness, and 94 Rogers and Newton swelling) were described at all sites, the predominant injuries described were site dependent; for example, tears were most frequently described on the pos- terior fourchette (n = 83) and fossa navicularis (n = 28), whereas abrasions were most frequently described on the labia minora (n = 66) and bruises were the most frequent injuries seen on the hymen (n = 28) (90). Adams and col- leagues found similar types and distributions of injuries among the adoles- cent complainants (14–19 years) they examined (132). In this population, tears of the posterior fourchette or fossa navicularis were the most common find- ings (40%). The studies of macroscopic findings among complainants of sexual assault have also found that most of the injuries detected are located on the external genitalia (133,134). Healing of lacerations of the posterior fourchette is predominantly by first intention, with no residual scarring being detected at follow-up assess- ments (90). Nonetheless, scarring may occur occasionally in these areas, but it is important not to mistake a linear vestibularis, a congenital white line iden- tified in the fossa navicularis (present in 25% of neonates), for a scar (135). Accidental injuries of the external genitalia of female children are well documented in the literature. The site and nature of the injury will depend on the type of trauma and the conformation of any object involved (136,137). Hymen The hymen must be examined in detail after an allegation of a nonconsensual penetrative act. When the hymen is fimbriated, this assess- ment may be facilitated by the gentle use of a moistened swab to visualize the hymenal edges. When the hymenal opening cannot be seen at all, application of a few drops of warm sterile water or saline onto the hymen will often reveal the hymenal edges. Foley catheters are also a useful tool to aid hymenal visu- alization in postpubertal females (138).

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