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By A. Kadok. Alderson-Broaddus College.

The other noncalcium and nonmetal-based binder extracellular potassium concentration generic accutane 40 mg. If transfusion of lanthanum carbonate has not been adequately stud- red blood cell products is necessary buy accutane 10mg with amex, attempts to secure ied in children and is generally not used in pediatric relatively fresh packed red blood cells should be made patients. Aluminum-containing binders are very effec- or washing the product should be considered. When 52 tive and were once the mainstay of phosphate binding units of packed red blood cells transfused in a pedi- in children. Methods to prepare a sevelamer vision should then be based on serial assessment of hydrochloride oral suspension have also recently been serum levels. If clinically appropriate, potassium salts can be added to the dialysate at concentrations 9. When it is evident that oral intake of nutrition is inad- Similar to hyperkalemia, hyperphosphatemia is a equate or projected to remain suboptimal, nutritional common electrolyte disturbance in oliguric or anuric support should be provided. Serum phosphorus occurs in two forms, tion is the preferred method of support for the critically organic and inorganic. Proposed benefits of enteral nutrition include principal circulating form and routinely assayed for intestinal trophism, reducing bacterial translocation, Chapter 9 Nutrition for the Critically Ill Pediatric Patient with Renal Dysfunction 133 stimulation of the immune system, and cost effective- lower phosphorus content when compared with other ness [2, 17, 32, 39]. A specific benefit infant formulas, however, and calcium supplementa- of enteral feeds is the potential for providing concen- tion may be necessary. This is of particular Nepro (Ross Products) are available for children and advantage to those patients with oliguric renal failure or adults and are designed for patients with reduced renal evolving or existing volume excess. Gastric residual volumes of feeds when gastric emptying is delayed, transpyloric and abdominal exams should be monitored closely feeds should be considered. Caloric density may be Good Start Supreme (Nestle Clinical Nutrition) has increased gradually in 2–4kcaloz−1 increments, and Table 9. To optimize digestibility, similar proportions of should be performed based on anticipated amino acid fat, protein, and carbohydrate as in the base formula losses and dextrose absorption from dialysis thera- should be provided. Electrolyte composition should be acid and small peptide losses may challenge the abil- guided by regular assessment of the patient’s labora- ity to supply adequate protein enterally. The underlying ill- ness and need for vasoactive medications may com- Optimal nutritional management of critically ill chil- promise gastrointestinal perfusion and function. An dren is challenging and becomes more complex should additional concern in the setting of chronic or acute there be an acute or chronic disturbance in renal func- renal failure is the potential detrimental effect of ure- tion. The provision of both adequate and appropriate mia on gastrointestinal motility, though this has been nutrition support should be viewed as a critical ele- studied primarily in patients on chronic dialysis [8, 28, ment in the therapeutic effort. Contraindications to enteral feeds include intesti- repeated evaluations of renal function, metabolic bal- nal obstruction, severe or protracted ileus, gastrointes- ance, volume status, and energy expenditure should be tinal ischemia, and hemodynamic instability. Chapter 9 Nutrition for the Critically Ill Pediatric Patient with Renal Dysfunction 135 continuous arteriovenous hemofiltration and total parenteral Take Home Pearls nutrition. Nutrition 13:45S–51S critical illness is to blunt the tendency towards negative 13. Nephrol Dial Transplant 22:2970–2977 parallels the severity of the underlying illness. American ing malnutrition in acute renal failure: A prospective cohort Society of Parenteral and Enteral Nutrition, Silver Spring, study. Kidney Int tive study of reducing the extracellular potassium concen- 65:999–1008 tration in red blood cells by washing and by reduction of 25. Nephrol Dial Transplant renal failure on continuous ambulatory peritoneal dialy- 9:287–290 sis using 99mTc-solid meal. Kidney Int following induction of systemic inflammatory response in 46:830–837 patients with severe sepsis or major blunt trauma. In: Byham-Gray L, amino acid balance during total parenteral nutrition and Wiesen K (eds) A clinical guide to nutrition care in kidney continuous arteriovenous hemofiltration in critically ill disease. Nutrition 18:445–446 ease as efficiently as calcium carbonate without increasing 40. Marin A, Hardy G (2001) Practical implications of nutri- serum calcium levels during therapy with active vitamin D tional support during continuous renal replacement therapy. Encephalopathy in childhood secondary to aluminum tox- Ann Surg 216:172–183 icity. Chapter 9 Nutrition for the Critically Ill Pediatric Patient with Renal Dysfunction 137 Postabsorptive rates and responses to epinephrine. J Clin ventilated, critically ill children during the early postinjury Invest 96:2528–2533 period. Clin Nutr agreement between indirect calorimetry and prediction equa- 26:677–690 tions using the Bland-Altman method. J Ren Nutr expenditure by continuous, online indirect calorimetry in 6:203–206 Tools for the Diagnosis 10 of Renal Disease K. This will provide strong clues to scores the importance of careful attention to ongoing the etiology of presenting renal and electrolyte abnormali- fluid, electrolyte, and biochemical balance. Predisposing existing medical with objective scientific measures or tools, which can be conditions, chronic medications, and knowledge reliably used to make a diagnosis and guide therapy.

Here order 30mg accutane mastercard, the mutated protein inhibits a cellular metabolic pathway and a therapeutic approach would be to delete expression of the mutated protein discount 5 mg accutane with mastercard. Therefore, a detailed understanding of the pathophysiology of the disease is required for designing gene therapy protocols. Both the genes in question need to be revealed as well as the cellular targets that could be utilized for therapy. For example, skin or muscle cells could be targeted for systemic diseases as opposed to liver cells. Regardless, the use of gene therapy to further understand disease pathophysiology could lead to the development of novel therapeutic approaches to disease remission. Animal Models of Disease As a correlate to the study of disease pathogenesis in the context of gene therapy, animal models of human disease provide the principles of disease pathogenesis (see Chapter 3). For gene therapy, the specific cells to be targeted for therapy as well as the number of cells needed for therapy can be elucidated. The following questions can be addressed by the use of experimental protocols in animals:Are transformed cells at a selective advantage or disadvantage? In addition, when the animal pathogenesis and human disease mani- festations are dissimilar, important keys to the human pathogenesis can still be obtained. Thus, as the testing ground of advancing molecular techniques, animal models or even the generation of transgenic animals should not be undervalued (see Chapter 3). With the report of the initial death of a patient in a gene therapy clinical trial, other issues have bubbled to the surface beyond adverse event reporting. These include patient safety and informed consent as well as federal oversight and coordination among agencies. Numerous investigations have led to some suggested recommendations for improvements in manufacturing and testing of gene transfer products and patient selection and monitoring. To instill public confidence in the research, adverse event data should be analyzed in a public forum. However, in the midst of this apparent disarray, the public has been emo- tionally stretched by the announcement and publication of the first success of gene therapy. Research efforts are needed to develop new vectors for gene transfer, to improve current viral and nonviral vectors, and to enhance genomic technology. Non- integrating vectors such as artificial chromosomes need to be further developed, and techniques using antisense strategies and ribozymes need to be enhanced. Studies are needed detailing gene expression that encompass regulatory elements both up- regulating and down-regulating gene expression. For instance, are we interested in survival as the only endpoint or is quality of life important as well? Thus, the field of gene therapy is in a growing phase where further advances will have a profound effect on our current understanding of mole- cular medicine. Phase I clini- cal trials will determine toxicity and efficacy in experimental systems. Thus, “gene therapy agents” that lower transcription of the gene for 5-a-reductase (which converts testosterone to dihydrotestosterone) might be developed to treat benign prostatic hyperplasia, for example, and later used to treat baldness. Specifically, for the case of “genetic enhancement” such as the case of baldness, ethical issues will be part of the equation in weighing risks vs. The targets of many current phase I therapies are genetic lesions causing disease in children and young adults. Successful gene therapy in these cases will save lives but not necessarily increase life expectancy or longevity. If gene therapies are to produce major increases in longevity, they will have to target diseases of the elderly, but which diseases? The holy grail of gene therapy would be to identify a transgene that modifies the biological clock and the aging process. The incidence of cardiovascular disease, diabetes, cancer, obesity, osteoporosis, dementia, and arthritis all increase with age. One approach to reducing the morbidity and mortality resulting from these condi- tions is to understand the biochemical pathways leading to each pathology in the context of aging and then develop interventions—using components of gene therapy. Longevity appears to be a polygenic characteristic to which individual genes make significant contri- butions. In a variety of biological systems, extended longevity is associated with enhanced ability to minimize oxidative stress. However, the first step in developing human gene therapies to delay aging will be to identify “longevity genes” in humans and other species. Screening of mutants with long life spans allowed the first longevity gene in nematodes, age-1, to be identified. Mutations in the clock genes lengthen the life of the worm from 9 days to almost 2 months. Clock genes are thought to set an internal pacemaker by regulating genes involved in metabolism. When clock gene mutations are combined with a mutation in daf-2 (a member of a different set of genes, which also affects nematode life span) worms, living at a leisurely pace, survive more than five times longer than normal. The human homologs of daf-2 are the insulin and insulinlike growth factor receptors, indicating that aspects of the regulatory system are evolutionarily conserved.

There are many effective ways to attract avian cli- Avian veterinarians should establish a program for ents best 20mg accutane, including adding birds to the logo on signs buy accutane 30mg line, visiting aviaries or multiple-bird households to per- stationery and business cards, placing avian maga- form preventive health screenings and aviary man- zines and client information in reception and exam agement evaluation (see Chapter 2). Fees newspaper clippings or articles help demonstrate a for aviary management consultations, multiple-bird clinic’s commitment to companion bird medicine examinations and large-volume laboratory work (Figure 7. Some clinics find that estab- Participating in the activities of bird clubs (meetings, lishing a library is well received by clients. Vide- newsletters, bird fairs) and volunteering to speak at otapes for in-clinic viewing can be made available school career days, civic groups and scout meetings and may include commercial tapes addressing avian are other excellent ways to achieve visibility and management or training, as well as short demonstra- credibility with companion bird clients. One suc- “National Geographic” episodes dealing with birds or 16 cessful program is called “parrot kindergarten. Sessions are conducted by a veterinarian, an avicul- turist and a bird trainer to provide experienced in- sight into avian health care, management and psy- chological stimulation. It is important for the beginning practitioner to be- come acquainted with local people who can serve as additional sources of information for individuals who keep birds. These people may include experienced avi- Staff Responsibilities culturists who are willing to share knowledge, “foster parents” who will temporarily take unwanted birds, Staff members play a major role in the success of any zoo aviary keepers, experienced ornithologists, librari- practice. They should be familiar with the clinic’s ans and the curators of natural history museums. Developing an office manual Finally, it is easiest to build a referral practice by that includes job descriptions, client instructions, assuring local veterinarians that their clients’ birds hospital protocol and general data on various species will be seen, but that their other pets will not. It is a of birds will serve as a reference text for the entire good idea to send the referring veterinarian a “Thank staff. Veterinary assistants should be expected to you for the referral” card and a written synopsis of keep the hospital clean, maintain a patient’s food and the diagnostic and treatment plan. It is especially water supply, fill prescriptions and perform routine important to maintain good communication with the procedures such as restraining, medicating and referring veterinarian if a client lives in another area grooming birds. All staff members should be encour- and the referring veterinarian will need to evaluate aged to have their own companion birds in order to the effect of therapy or to provide further medica- better relate to the clients and their birds. Treatment and follow-up visits should be done critical that staff members’ and clinic birds be locally whenever possible. If the ambient temperature is less than 60-75°F, it is recommended that the car be pre-warmed as well. Likewise, if ambient temperature exceeds 90°F, care must be taken to prevent hyperthermia. A bird brought into the hospital on its owner’s arm is an accident waiting to happen (Figure 7. There- fore, it should be hospital policy that all animals be maintained in an enclosure while in the reception area. If it is not possible to bring a bird’s enclosure, a small animal carrier can be modified with the addi- tion of a perch. It is helpful for the staff to introduce themselves to new clients and to tell them what to expect during the office visit. The technician should weigh the bird, discuss husbandry with cli- ents and assist with restraint during the examina- tion. At many clinics, a client can make an appoint- ment with the veterinary technician for routine grooming procedures such as wing clips, weight monitoring and beak and nail trims. Client information about the diet and home environment information brochures are available in the waiting room and in the examination room (courtesy of Cathy Johnson-Delaney). The technician should Communicating with the Client take a Polaroid snapshot of the client and bird for the When a client calls for an appointment, the recep- bird’s medical record. The client should be provided a tionist must instruct the client on the proper way to folder-type health record with a pocket to maintain transport the bird to the clinic so that an evaluation receipts and examination certificates. The serve as a reminder that birds need the same kind of water dish should be emptied before transport, but routine preventive medical care as other pets. The client should also be instructed to collect are recommended with emphasis on detecting sub- several fresh fecal samples at home by placing plastic clinical problems (see Chapter 8). The samples should be folded give the new client a “New Bird Kit” on the initial in the plastic and refrigerated until transport to the visit. A paper towel placed over the enclosure sub- folder, client education materials, a hemostatic strate will help identify fresh droppings produced agent, a telephone sticker with the phone numbers of during the trip to the hospital. The client should also the clinic and recommended emergency clinic, sam- bring previous medical records, samples of the nor- ples of recommended avian foods and subscription mal diet and samples of any abnormal discharges. Hospitalization Protocol Clients apprehensive about hospital- izing their birds may feel more at ease if they are introduced to the staff members who will be caring for the bird and shown where their bird will be housed. Additionally, birds being provided such as heat, light, music transported from one area of the hospital to another should be placed back in an enclosure and visibility of humans. Visitation to prevent accidental releases and injuries (right) (courtesy of Cathy Johnson-Delaney). This helps emphasize the clinic’s com- to its family and becomes depressed when separated mitment to personalized attention for each patient. On the other hand, if the The medical record system used in most small ani- bird has a contagious disease or is recovering from a mal clinics can be modified for avian patients.

Oligonu- cleotide bearing sequence complementarly to the chromosomal target are annealed to the specific site forming a triple helix at regions that are rich in purines or pyrimidines accutane 20 mg low price. In some cases cheap 10mg accutane overnight delivery, the oligonucleotide may contain a reactive modification that is activated by light. This reaction modifies the target so that block to transcription or replication is blocked. Hence, the structure is a stable, strong duplex that enters the nucleus efficiently. These molecules have been shown to catalyze gene targeting by mediating gene conversion events. In mammalian cells, point mutations are converted at a frequency high enough to detect without metabolic selection, and it appears that there is no limitation as to the sites of targeting available to the chimeric oligonucleotides. However, the most important discovery of these molecules comes from their wide- ranging effectiveness in bacterial, plant, and mammalian cells. Due to its intracellular stability, these molecules cat- alyze gene conversion at a frequency that exceeds most predicted levels. It is not uncommon for bacterial targets to be converted at a rate of 1 to 5%, meaning that 5 cells in 100 receiving the chimera undergo gene conversion. A simple example using an episomal tetracycline gene as a target serves to illustrate the technique nicely. A chimeric oligonucleotide designed to mediate the correction is then transferred into the plasmid-containing bacterial cells. After a short recovery in medium containing tetracycline, the cells are grown for 16h in liquid medium. This experimental system addresses a series of impor- tant questions and concerns of genetic targeting: Is the conversion efficient? Is the conversion stably transmitted to daughter cells and can the genetic change be prop- agated? The answers to all of these questions is, presumably, “yes,” when chimeric oligonu- cleotides are used in bacterial cells. Early attempts included increasing the length of the homology shared by the fragment and the genomic target. The topology of the targeting vehicle, usually a plasmid construct, was also modified but failed to improve the frequency of targeting specificity. Genomic Insertion To keep things in perspective, one must consider naturally occurring events that lead to insertions into the genome. The best example of this molecular process involves the integrative activity of viruses. As described earlier in this chapter and others, these viruses infect dividing cells at a high frequency but integrate randomly. Such observations have led to frustration among investigators hoping to use retroviruses for gene therapy. In some strategies, for example, precise integration would be helpful to achieve func- tional results. However, the central issue is that the cell does not naturally promote site-specific integration. Whether it is overwhelmed by the biological effort of the virus to integrate frequently or whether the enzymatic machinery driving homol- ogous insertion is naturally suppressed is not clear. This integrative event is catalyzed by the virally encoded Rep protein, an enzyme used to replicate the virus in the cell. Thus, a virally encoded protein, not a cellular enzyme, promotes site-specific targeting. Biochemical studies have shown that the Rep protein acts as a dimer, one subunit binding to the viral sequence and the other to the homologous viral-like sequence in the chromosome. The requirement for Rep binding sequences in both templates will clearly limit this approach. Hence two examples with naturally integrative elements (retroviruses and adenoassociated virus) have led investigators to conclude that homologous integration in mammalian cells is not a preferred or even a natural reaction. Gene Targeting: Gene Insertion or Gene Replacement in Mammalian Cells With this as a background, workers have attempted to translate the genetic obser- vations, and in some cases molecular tricks, found to work in lower eukaryotes or bacteria into the mammalian cell targeting arena. An early observation by yeast geneticists was that a double break in the homologous region of the targeting molecule elevated the frequency of site-specific integration. It had been widely accepted that double-stranded breaks promote homologous recombination even in mammalian cells, but the continual low frequency of specific events has persisted. To improve the frequency and develop reliable test systems, several strategies have emerged.

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