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6 Special Considerations PROTOCOL REVIEW One of the many important responsibilities of an institutional animal care and use committee (IACUC) is to review the protocols of research projects in which dogs will be used (9 CFR 2.31; PHS, 1986~. The proto- col-review mechanism is designed to ensure that investigators consider the care and use of their animals and that protocols comply with federal, state, and institutional regulations and policies. In addition, the review mecha- nism enables an IACUC to become an important institutional resource, as- sisting investigators in all matters involving the use of animals. Although the discussion below is directed to the use of dogs in research, the review requirements apply to all vertebrate species. Each research protocol must completely (but concisely) delineate the proposed study, including a description of each of the following: the purpose of the study; the rationale for selecting dogs as the research subjects; the breed, age, and sex of the dogs to be used; the numbers of dogs in various groups of the protocol and the total number to be used; experimental methods and manipulations; experimental manipulations that will be performed repeatedly on an individual dog; 76

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SPECIAL CONSIDERATIONS preprocedural and postprocedural care and medications; procedures that will be used to minimize discomfort, pain, and dis- tress, including, where appropriate, the use of anesthetics, analgesics, tran- quilizers, and comfortable restraining devices; the euthanasia method, including the reasons why it was selected and whether it is consistent with the recommendations of the American Veteri- nary Medical Association Panel on Euthanasia (AVMA, 1993, et seq.~; the process undertaken to ensure that there are no appropriate in vitro alternatives, that there are no alternative methods that would decrease the number of animals to be used, and that the protocol does not unneces- sarily duplicate previous work; and the qualifications of the investigators who will perform the proce- dures outlined. One approach used by IACUCs is to have a scientifically knowledge- able member thoroughly review the protocol. The reviewer contacts the investigator directly to clarify issues in question. Later, at an IACUC meet- ing, the reviewer presents and discusses the protocol and relates discussions with the investigator. Changes or clarifications in the protocol that have resulted from the reviewer's discussions with the investigator are submitted to the IACUC in writing. After presentation of the protocol, the reviewer recommends a course of action, which is then voted on by the IACUC. Another kind of protocol review (which is especially effective in small institutions with few grants) is initial review by the entire IACUC; results are generally available to the investigator within a short period. Several outcomes of protocol review are possible: approval, approval contingent on receipt of additional information (to respond to minor prob- lems with the protocol), deferral and rereview after receipt of additional information (to respond to major problems with the protocol), and with- holding of approval. If approval of a protocol is withheld, an investigator should be accorded due process and be given the opportunity to rebut the IACUC's critique in writing, to appear in person at an IACUC meeting to present his or her viewpoint, or both. It is also important that provision be made for expedited review, in which a decision is reached within 24-48 hours. Expedited reviews should be used only for emergency or extenuat- ing circumstances. When a protocol is submitted for expedited review, each member of the IACUC must have an opportunity to review it and may call for a full committee review before approval is given and before animal work begins (McCarthy and Miller, 1990~. The question of protocol review for scientific merit has been handled in a variety of ways by IACUCs. Many protocols are subjected to extensive, external scientific review as part of the funding process; in such instances, the IACUC can be relatively assured of appropriate scientific review. In 77

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78 DOGS: LABORATORY ANIMAL MANAGEMENT the case of studies that will not undergo outside review for scientific merit, many IACUCs require signoff by the investigators, department chairmen, or internal review committees; this makes the signer responsible for providing assurance that the proposed studies have been designed and will be per- formed "with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society" (NRC, 1985, p. 82; PHS, 1986, p. 27~. Occasionally, IACUC members and investigators differ as to the relevance of proposed studies to human and animal health and the advancement of knowledge. Each institution should develop guidelines for dealing with this potential conflict. RESTRAINT Some form of restraint is generally necessary to control a dog during a procedure (see guidelines in NRC, 1985, p. 9~. The method used should provide the least restraint required to allow the specific procedure to be performed properly, should protect both the dogs and personnel from harm, and should avoid causing distress, physical harm, or unnecessary discom- fort. In handling and restraining dogs, it is helpful to understand species- typical behavior patterns and communication systems. A small or medium-size dog can be picked up by placing one hand under the chest and abdomen while restraining the head with a leash. Lift- ing a large dog might require two people. It is important to remember that males are sensitive to touch near their genitalia. Minor procedures, such as taking a rectal temperature or administering a subcutaneous injection, can usually be accomplished by one person using minimal restraint. During venipuncture, sufficient restraint should be used to avoid repeated needle insertions and to prevent the development of painful hematomas. Kesel and Neil (1990) detail methods for handling and restraining animals. If dogs are to be restrained frequently or for long periods or if the restraint method used is especially rigorous, it might be necessary to train them to tolerate the restraint. Training sessions should use positive-rein- forcement techniques; negative-reinforcement techniques are not desirable. Physical abuse (9 CFR 2.38f2i) and food or water deprivation (9 CFR 2.38f2ii) must not be used to train, work, or handle dogs, although food and water may be withheld for short periods when specified in an IACUC-approved protocol (9 CFR 2.38f2ii). SPECIAL CARE FOR ANIMAL MODELS The remainder of this chapter deals with some common uses of labora- tory dogs in which aspects of care vary from the general guidelines pro- vided in previous chapters. It is not intended to present an exhaustive list

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SPECIAL CONSIDERATIONS 79 of canine models that require special housing and husbandry, but rather to provide the reader with different types of canine models that can serve as examples of how housing and husbandry can be modified to achieve animal well-being. The suggestions offered here are not to be construed as the only ones possible. The committee recognizes that not every research pro- cedure and circumstance can be anticipated, and it assumes that sound pro- fessional judgment, good veterinary practices, and adherence to the spirit of this guide will prevail in unusual situations. The final subsection of this chapter introduces the reader to the tech- nique of somatic cell gene therapy. Many disorders of dogs, like those of humans, are caused by single-gene mutations. Scientists are working to develop techniques to cure these disorders permanently by replacing mutant genes with normal ones. For many reasons (see Chapter 2), the dog is an ideal model for evaluating the safety and efficacy of gene therapy. Aging Clinical Features Life expectancy and disease incidences vary among breeds of dogs; therefore, it is not possible to state a specific age at which dogs become old. Common laboratory dogs, such as beagles, begin some aging changes when they are 8-10 years old. Such physical features as graying of the haircoat, especially around the face, are often apparent as aging begins. As dogs age, they tend to become less active and to exhibit such signs of mental deterioration as poor recognition of caretakers, excessive sleep- ing, and changes in personality. Senile plaques, similar to those found in humans with senile dementias, have been reported in the brains of old dogs (Wisniewski et al., 1970~. Various forms of arthritis, spondylosis, and degenerative joint disease are common and contribute to problems in mobil- ity and to the apparent diminution of mental alertness. Older dogs might decrease their daily food intake, become slow eaters, or become irregular in their eating habits. Dental problems including periodontal disease, tooth abscesses, and oral-nasal fistulas increase; the importance of these prob- lems is probably underestimated (Tholen and Hoyt, 1983~. Dogs more than 6 years old develop lenticular sclerosis, which results in a bluish appear- ance within the pupil. Visual acuity decreases with age and is often associ- ated with cataracts, secondary glaucoma, and other diseases (Fischer, 1989~. There is also apparent hearing loss. Atrophy of the thyroid gland and an increased number of thyroid tu- mors have been reported, and signs of hypothyroidism are common (Haley et al., 1989; Milne and Hayes, 19811. Thyroid atrophy and the propensity of older dogs to develop hypothermia might be related (B. A. Muggenburg, l

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80 DOGS: LABORATORY ANIMAL MANAGEMENT Inhalation Toxicology Research Institute, Lovelace Biomedical and Envi- ronmental Research Institute, Albuquerque, N.M., unpublished). A decreased response to antigens and changes in lymphocyte function might indicate that the older dog is less able to resist infectious diseases (Bice and Muggenburg, 1985~. Some changes in common blood-cell measures and serum chemistry become important when these are used for diagnosis (Lowseth et al., 1990a). The incidence of neoplasia increases strikingly (MacVean et al., 1978~; for example, lung tumors, nearly unknown in young dogs, can reach an inci- dence as high as 10 percent in dogs over 10 years old (Ogilive et al., 1989~. Pulmonary function decreases with age because of reduced lung volumes and decreased elasticity (Mauderly and Hahn, 1982~. Chronic renal dis- eases often occur and require frequent monitoring. Chronic heart disease is also fairly common, and clinical signs can appear suddenly in old dogs. Husbandry and Veterinary Care Housing and environment. Accommodation should be made for dogs that have problems moving comfortably on floor grates or through guillo- tine-like doors in kennel buildings. Because of their decreased mobility and impaired thermoregulatory function, aging dogs with access to outdoor ar- eas should be checked frequently to be certain that they are able to get inside to escape the cold or heat. Automatic watering devices might be- come difficult to use; for some old dogs, it might be necessary to switch to water pans placed on the floor. Nutrition. Differentiation between age-related and disease-caused changes in eating habits might be difficult. It is important that animal-care person- nel become familiar with and closely monitor daily eating habits of older dogs. Frequent checking and recording of body weights can help in assess- ing whether food intake is adequate. Changes in diet are sometimes dic- tated by the clinical diagnosis of disease (e.g., a low-protein diet for chronic, progressive renal disease and a low-sodium diet for chronic heart failure). Physical characteristics of food can affect dental hygiene. Soft and wet food fed over many years can contribute to dental disease. Feeding dry dog food and providing hard objects for chewing can be helpful in the long-term management of dental problems. Routine dental care, including the removal of calculus and polishing, is essential. Veterinary care. The extent of chronic disease problems in older dogs requires more intensive veterinary care, extensive diagnostic investigations, and good nursing. Dosages of some medications might have to be reduced, because drugs are commonly metabolized more slowly in old than in young adult dogs. Such drugs as digoxin should be monitored by measuring blood

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SPECIAL CONSIDERATIONS 81 concentrations to decrease the risk of overdosing (De Rick et al., 1978~. A useful reference on geriatric veterinary medicine is Geriatrics and Geron- tology (Goldston, 19899. Reproduction Bitches. Andersen and Simpson (1973) have described reproductive senescence in beagle bitches. Intact bitches exhibit irregular estrous cycles, accompanied by decreased fertility, and prolonged periods of anestrus. The mortality rate is higher among puppies born to older bitches than among puppies born to bitches less than 3 years old. The most common pathologic condition of the uterus of aged bitches is pyometra (Andersen and Simpson, 1973; Jarvinen, 1981; Whitney, 1967~. Vaginal fibromuscular polyps are also common (Andersen and Simpson, 1973~. The age-specific incidence of mammary gland neoplasms in intact beagle bitches continues to increase throughout life (Taylor et al., 1976~. Dogs. Aging dogs have testicular atrophy and often develop prostatic hypertrophy and hyperplasia and have episodes of prostatitis (Lowseth et al., l990b). There are also metaplastic changes in the bladder (Lage et al., 1989~. Cardiovascular Diseases Congenital Heart Defects Clinical Features Dogs with hereditary cardiovascular malformations have been used to investigate the role of genetic and embryologic factors in the cause and pathogenesis of congenital heart defects, including hereditary patent ductus arteriosus, conotruncal defects (e.g., ventricular septal defect, tetralogy of Fallot, and persistent truncus arteriosus), discrete subaortic stenosis, and pulmonary valve dysplasia. Congenital heart defects in dogs have been summarized by Buchanan (1992) and Eyster (19923. Table 6.1 describes and lists the clinical signs of selected heart defects. Each of those defects is transmitted as a lesion-specific genetic defect in one or more breeds. A model for each defect has been developed at the University of Pennsylvania School of Veterinary Medicine by selective breeding of affected dogs (Patterson, 1968), as follows: patent ductus arteriosus, toy and miniature poodles (Acker- man et al., 1978; De Reeder et al., 1988; Gittenberger-de Groot et al., 1985; Knight et al., 1973; Patterson et al., 1971~; conotruncal defects, keeshonden (Patterson et al., 1974, 1993; Van Mierop et al., 1977~; discrete subaortic

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82 DOGS: LABORATORY ANIMAL MANAGEMENT TABLE 6.1 Selected Congenital Cardiac Defects in Dogs Defect Description Clinical Signs Patent ductus Failure of ductus arteriosus to Vary with size of duct and arteriosus close after birth. If pulmo- pulmonary vascular resistance nary vascular resistance is from subclinical to heart low, blood flows through failure. Early signs include ductus from left to right. Pul- poor growth, coughing, and monary hypertension and left dyspnea. Aneurysm can occur ventricular hypertrophy result at site of ductus arteriosus. unless ductus opening is small. Polycythemia occurs in If ductus is large and pulmonary cyanotic dogs with a large vascular resistance is high, put- patent ductus arteriosus lmonary arterial pressure can (PDA), pulmonary hyper exceed aortic pressure, and blood tension, and right to left will flow from right to left, sending blood flow through the PDA. venous blood into ascending aorta. Conotruncal defects Ventricular Failure to complete formation of Vary with size of defect from septal the conotruncal septum results in subclinical to signs of defect ventricular septal defects (VSDs) respiratory and right-side of varied size, involving the lower heart failure, including and middle portions of the crista cyanosis, dyspnea, weakness, supraventricularis (Type I, sub- and anorexia. arterial VSD). Pups with large VSDs usually die from pulmonary edema in the neonatal period. Smaller VSDs are compatible with long life unless complicated by pulmonary hypertension and congestive heart failure. Tetralogy of Consists of pulmonic stenosis Fallot (valvular, infundibular, or both), conal ventricular septal defects, dextroposition of aorta with overriding of ventricular septum, and right ventricular hypertrophy. Some dogs have pulmonary valve atresia (pseudo-truncus arteriosus). Persistent truncus arteriosus Depend on severity of pul . . . mon1c stenosis anc ventrlc- cular septal defect. Can include decreased body size, fatigue, cyanosis, and secondary polycythemia. Severe but rare anomaly. Complete Cyanosis and dyspnea. Dogs failure of septation of conus and rarely survive neonatal period. truncus regions, producing large conal ventricular septal defect and single arterial outlet vessel.

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SPECIAL CONSIDERATIONS TABLE 6.1 Continued 83 Defect Description Clinical Signs Discrete subaortic Narrowing of left ventricular out- Vary with degree of stenosis stenosis flow tract, most commonly by from asymptomatic to poor fibrous ring just below aortic growth, exercise intolerance, semilunar valves, with concomi- syncope, ventricular tent obstruction of blood flow, arrhythmias, pulmonary left ventricular hypertrophy, edema, and sudden death. and increased left ventricular pressure. Pulmonary valve Varies from mild thickening of Vary from asymptomatic to dysplasia leaflets surrounding narrowed dyspnea, fatigability, and pulmonary orifice to complete right-side heart failure. fusion of leaflets and doming of valve. Interferes with emptying of right ventricle. stenosis, Newfoundlands (Patterson, 1984; Pyle et al., 1976), and pulmo- nary valve dysplasia, beagles (Patterson, 1984; Patterson et al., 1981~. Conotruncal defects in the keeshond breed are determined by the effect of a single major gene defect (Patterson et al., 19931. Subaortic stenosis in Newfoundlands also appears to be monogenic with variable expression (Patterson, 1984~. Patent ductus arteriosus and pulmonary valve dysplasia are inherited in a non-Mendelian pattern. Husbandry and Veterinary Care Animals with cardiac defects often require exercise restriction to avoid cyanosis and congestive heart failure. The need for restriction must be decided for each dog on the basis of cardiac status. If the clinical manifes- tations of severe defects (e.g., respiratory distress, severe cyanosis, and congestive heart failure) cannot be relieved with appropriate surgical meth- ods or cardiovascular drugs (e.g., cardiac glycosides and diuretics), the dog should be humanely killed (see Chapter 5~. Reproduction Only dogs with mild to moderate cardiac defects or those in which the defects have been surgically corrected should be selected for breeding. Se- verely affected dogs do not survive to breeding age, or they develop clinical manifestations that preclude their use for reproduction (e.g., marked cyanosis

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84 DOGS: LABORATORY ANIMAL MANAGEMENT and congestive heart failure). Methods of modern clinical cardiology- including auscultation, radiography, echocardiography, cardiac catheterization, and angiocardiography are necessary for accurate diagnosis and evalua- tion of the severity of defects in candidates for breeding. Therefore, appro- priate facilities and equipment and personnel qualified to use such equip- ment must be available before a breeding colony is established. Once it is established, the health status of breeding stock and their offspring must be carefully monitored. Induced Heart Defects Clinical Features Many animal models of cardiac disease are surgically induced in physi- ologically normal animals. Aims of the research protocol and humane con- siderations must often be carefully balanced to ensure that the maximal amount of information is derived from each animal. Surgically induced models can be broadly divided into models of vol- ume or pressure overload produced by creating valvular or interchamber defects, models of ischemic injury, and models of arrhythmia (Gardner and Johnson, 1988~. Long-term management of these models Carl be difficult because they are frequently on the verge of physiologic decompensation and at risk of sudden death. Table 6.2 lists the signs of cardiac failure. TABLE 6.2 Clinical Signs of Heart Failure in Dogs Type of Heart Failure Clinical Signs Left-side Right-side Generalized Exercise tolerance decreases. Inappropriate dyspnea follows exercise. Pulmonary venous pressure increases, initially causing pulmonary and bronchial congestion and reflexogenic bronchoconstriction. Repetitive coughing follows exercise. Orthopnea, with a reluctance to lie down; restlessness at night; and paroxysmal dyspnea are common. In severe failure, pulmonary edema, severe dyspnea at rest, and rates on auscultation become evident. Systemic venous congestion occurs with engorgement of jugular veins. Liver and spleen are enlarged and often palpable. Fluid retention is usually first manifested as ascites; subcutantous edema, hydrothorax, or hydropericardium can follow. Disturbances of gastrointestinal function, with diarrhea, can occur. Signs of both left- and right-side failure occur.

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SPECIAL CONSIDERATIONS Husbandry and Veterinary Care 85 The management of chronic dog models of induced heart failure is most successful if the approach used is interdisciplinary, involving cardiologists, surgeons, and veterinary-care staff. Goals of long-term management in- clude identifying potential complications, selecting therapeutic regimens, and developing long-term monitoring protocols. The following general guidelines should be tailored to the type of disorder induced, the dogs' well-being, and the goals of the research protocol. Postoperative care. Postoperative care depends on the type of heart disease induced. Medical management should continue after successful recovery from surgery because a specific surgical protocol does not always produce a physiologically consistent model. Some dogs achieve a stable, compensated postoperative condition; others undergoing the same proce- dure develop signs of acute heart failure immediately after surgery. Careful monitoring on the days after surgery is critical. Meticulous physical examinations should be performed on physiologically stable dogs at least once a day until they have recovered from surgery. Physiologically unstable dogs should be examined more often. Vital signs should be moni- tored, and particular attention should be given to physical findings related to the cardiovascular system. Mucous membrane color, capillary-refill time, and temperature of extremities can be abnormal if peripheral perfusion is seriously impaired. The pulse quality of the femoral artery can be used to assess systemic perfusion. Auscultation should be used to detect abnormal cardiac sounds, and electrocardiography should be performed to diagnose arrhythmias. Assessment of respiratory rate and depth should be combined with careful auscultation of all lung fields to detect early signs of pulmo- nary complications. Echocardiography, if available, can be used to evaluate cardiac function and contractility. Good nursing care is important. Special diets, such as canned dog food or dry food mixed with chicken broth, can be offered to encourage food intake. Ideally, dogs should be housed in a dedicated recovery room and returned to the regular housing area only when they are physiologically stable and have recovered fully from surgery. Decreased exercise tolerance secondary to diminished cardiac reserve might affect the extent of activity that a dog can withstand. Complications. Potential complications associated with surgical and catheterization procedures should be anticipated, including infection of the operative sites bacteremia, and endocarditis. Dogs at high risk for compli- cations are the ones that undergo serial catheterization procedures and those with bioimplants, such as prosthetic valves and pacemakers (Dougherty,

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86 DOGS: LABORATORY ANIMAL MANAGEMENT 1986~. Baseline monitoring should include scheduled physical examina- tions and complete blood counts (CBCs). A blood culture should be sub- mitted to the laboratory for any animal with a persistent fever or an inter- mittently increased temperature. If infection is suspected, a broad-spectrum antibiotic, such as one of the cephalosporins, should be administered pend- ing receipt of culture and sensitivity results. Banding of the great vessels with various materials is a standard proce- dure for producing volume- and pressure-overload models of ventricular hypertrophy, coarctation of the aorta, and obstruction of right ventricular outflow. Vessel erosion caused by the material used (Gardner and Johnson, 1988) and hemorrhage secondary to banding procedures are common com- plications that should be included in the differential diagnosis of any banded animal that suffers an acute onset of lethargy, paleness of the mucous mem- branes, or dyspnea. Those are also clinical signs of heart failure, so it is important to perform auscultation of the chest and suitable diagnostic tests, such as radiography or thoracentesis, to make an accurate diagnosis. A dog that is hemorrhaging should be euthanatized. Surgical procedures used to induce cardiac disease invariably cause disruption of the endothelium and put the dogs at risk for thrombosis and embolism. Dogs undergoing cardiac catheterization or surgery of the car- diac valves are at greatest risk. Clinical signs reflect the organs involved. tong-term monitoring. In a study of extended duration, assessment of each dog's general health and cardiovascular system should be continuous. The type and frequency of examinations will depend on whether the model is physiologically stable or unstable. For example, a dog with induced mitral regurgitation, which is defined as a 50 percent reduction in forward stroke volume and a pulmonary capillary wedge pressure of 20 mm Hg, can develop life-threatening pulmonary edema (Nakano et al., 1991; Swindle et al., 1991~. Frequent monitoring and auscultation are required to detect early signs of respiratory compromise so that the dog will not die before therapy can be initiated or the dog can be studied. Similarly, a dog with induced right ventricular pressure overload requires frequent monitoring because decreased coronary blood flow can lead to acute right-side heart failure (Fixler et al., 1973; Vlahakes et al., 1981~. Conversely, a stable model of left ventricular hypertrophy can be produced in 8-week-old pups by aortic banding, which causes a systolic pressure gradient of 15-20 mm Hg (O'Kane et al., 1973~. Dogs with induced tricuspid valve insufficiency can tolerate increased venous pressure and a slight reduction in cardiac output for years, although some develop ascites and reduced serum albumin (Arbulu et al., 1975~. These models require less frequent monitoring. Equipment. Follow-up care and monitoring require appropriate equip

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120 DOGS: LABORATORY ANIMAL MANAGEMENT that will restore suppressor-gene function or neutralize the function of acti- vated oncogenes; and to induce tolerance to transplantation antigens by transferring genes that code for such antigens (Anderson, 1984~. The use of the dog as a preclinical, large, random-bred animal model has set the stage for clinical gene therapy. A number of target tissues for gene therapy have been used; this section will cover three of them. Hematopoietic Stem Cells In preparation for gene transfer, marrow is aspirated while the dog is under general anesthesia. The hair over the shoulder and hip joints is clipped. The skin is cleaned with povidone iodine, washed with 70 percent ethyl alcohol, and cleansed with sterile Ringer's solution. Under sterile conditions, a needle 20 cm long and 2.5 mm in internal diameter is inserted into the marrow cavity through the proximal intertubercular groove of the humerus or trochanteric fossa of the femur. The needle is then connected with polyvinyl tubing to a suction flask, and marrow is aspirated by placing a suction flask, which contains tissue-culture medium and preservative-free heparin, under negative pressure with a pump. The procedure can be com- pleted on all four limbs in approximately 20 minutes, during which 70-80 ml of a mixture of blood and bone marrow is collected. The marrow sus- pension is then passed through stainless-steel screens with 0.307- and 0.201- mm mesh diameters. A 1 ml sample is taken for marrow cell counts, and the remainder of the marrow is placed in plastic containers. The aspiration procedure is well tolerated without any sequelae. walking unimpaired after recovery from anesthesia. Nucleated marrow cells are then cocultivated with virus-producing packaging cells at a ratio of 2:1 for 24 hours in 850-ml roller bottles. The gene- containing vector is replication-defective. Retrovirus-producing packaging cells are seeded in roller bottles 48 hours before the addition of marrow and are cultured in vitro with established techniques. After cocultivation, mar- row cells are used to boost long-term cultures established 1 week earlier. The cultures are harvested after 6 days of incubation, and marrow cells are carefully removed without dislodging the virus-producing packaging cells, washed, resuspended in serum-free medium, and infused intravenously into the dog from which the marrow was taken. In preparation for the infusion, the dog is exposed to total-body irradia- tion to create room for the infused marrow to seed. Total-body irradiation is administered at doses of 4-10 Gy and is usually delivered at a rate of 7 cGy/minute from two opposing cobalt-60 sources. For that purpose, an unanesthetized dog is housed in a polyurethane cage that is midway be- tween the two cobalt-60 sources. The long axis of the cage is perpendicular to a line between the sources. After irradiation, the dog is returned to the Dogs are capable of

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SPECIAL CONSIDERATIONS 121 animal-care facility for supportive care. Total-body irradiation can cause nausea, vomiting, and diarrhea. Its destruction of normal marrow leads to a disappearance of red cells, white cells, and platelets. The temporary ab- sence of those blood components produces a risk of anemia, infection, and bleeding that persists unless the dog receives a marrow graft and the graft begins to function. Dogs are monitored daily and receive parenteral fluids and electrolytes as required. Appropriate preoperative and postoperative antibiotics are routinely used to prevent and treat infections. Platelet and red-cell transfusions are given as needed. Marrow-graft function is moni- tored by evaluating daily blood counts. The success of gene transfer can be assessed by repeated aspiration of marrow under general anesthesia and examination of the samples for the appropriate marker gene with culture techniques, the polymerase chain re- action, or other appropriate methods (Stead et al., 1988~. Peripheral blood cells can be tested in a similar manner, as can lymph node lymphocytes and pulmonary macrophages (Stead et al., 1988~. Skin Keratinocytes Skin keratinocytes provide another good target for gene insertion. For some gene products, such as adenosine deaminase, gene transfer can take place in any replicating tissue. A 2 x 1.5-cm skin biopsy is obtained from the recipient under general anesthesia. Keratinocytes are derived from the biopsy material and cocultivated in vitro with replication-deficient retroviral vectors that contain the gene of interest. Keratinocytes are then cultured in a liquid-air interface culture, which gives rise to the various layers of skin in an in vitro system. After some time in culture, the skin grown in vitro is transplanted into a prepared bed on the flank of the dog under general anesthesia. The transplant site is treated with topical antibiotic powder, protected by nonadhering dressing, and inspected daily by the investigators. Generally, the skin grows in and is functional in 3-4 weeks. Punch biopsies of 2-3 mm allow assessment of gene transfer (Flowers et al., 1990~. Smooth Muscle Transplantation Because of their location, genetically modified vascular smooth muscle cells can be particularly useful for the treatment of some diseases (e.g., hemophilia). Studies have demonstrated that vascular smooth muscle cells are easily obtained, cultured, and genetically modified and replaced and provide a good target tissue for gene therapy that involves both secreted and nonsecreted proteins (Lim et al., 1991~. A segment of femoral artery or vein is surgically removed from a dog for preparation of smooth muscle cell cultures. The procedure of removing femoral artery and vein segments will

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22 DOGS: LABORATORY ANIMAL MANAGEMENT not compromise the dog, because there is extensive collateral circulation in this region. With the dog under general anesthesia, as long a segment of vessel as possible (at least 2 cm) is isolated from the circulation with liga- tures. Any side branches in the two ends are permanently ligated before the vessel is removed. The smooth muscle cells are isolated, cultured, and infected with replication-defective amphotropic retroviruses that carry the genes of interest, in accordance with National Institutes of Health recombi- nant-DNA guidelines. The genetically modified smooth muscle cells are returned to the animal from which they were obtained. With the dog once again under general anesthesia, the transduced cells are seeded into the left and right carotid arteries and into the remaining femoral arteries (Lim et al., 1991~. REFERENCES Ackerman, N., R. Burk, A. W. Hahn, and H. M. Hayes, Jr. 1978. Patent ductus arteriosus in the dog: A retrospective study of radiographic, epidemiologic, and clinical findings. Am. J. Vet. Res. 39:1805-1810. Andersen, A. C., and M. E. Simpson. 1973. The Ovary and Reproductive Cycle of the Dog (Beagle). Los Altos, Calif.: Geron-X, Inc. 290 pp. Anderson, W. F. 1984. Prospects for human gene therapy. Science 226:401-409. Arbulu, A., S. N. Ganguly, and E. Robin. 1975. Tricuspid valvulectomy without prosthetic replacement: Five years later. Surg. Forum 26:244-245. AVMA (American Veterinary Medical Association). 1993. 1993 Report of the AVMA Panel on Euthanasia. J. Am. Vet. Med. Assoc. 202:229-249. Beierwaltes, W. H., and R. H. Nishiyama. 1968. Dog thyroiditis: Occurrence and similarity to Hashimoto's struma. Endocrinology 83:501 -508. Bell, S. C., S. D. Carter, and D. Bennet. 1991. Canine distemper viral antigens and antibodies in dogs with rheumatoid arthritis. Res. Vet. Sci. 50:64-68. Ben, L. K., J. Maselli, L. C. Keil, and I. A. Reid. 1984. Role of the renin-angiotensin system in the control of vasopressin and ACTH secretion during the development of renal hyper- tension in dogs. Hypertension 6:35-41. Bice, D. E., and B. A. Muggenburg. 1985. Effect of age on antibody responses after lung immunization. Am. Rev. Respir. Dis. 132:661-665. Blum, J. R., L. C. Cork, J. M. Morris, J. L. Olson, and J. A. Winkelstein. 1985. The clinical manifestations of a genetically determined deficiency of the third component of comple- ment in the dog. Clin. Immunol. Immunopathol. 34:304-315. Bonagura, J. D., ed. 1986. Section 4: Cardiovascular diseases. Pp. 319-424 in Current Veterinary Therapy. IX. Small Animal Practice, R. W. Kirk, ed. Philadelphia: W. B. Saunders. Bovee, K. C., M. P. Littman, F. Saleh, R. Beeuwkes, W. Mann, P. Koster, and L. B. Kinter. 1986. Essential hereditary hypertension in dogs: A new animal model. J. Hypertens. 4(Suppl. 5):S172-S173. Brooks, D. P., and T. A. Fredrickson. 1992. Use of ameroid constrictors in the development of repin-dependent hypertension in dogs. Lab. Anim. Sci. 42:67-69. Brooks, D. P., T. A. Fredrickson, P. F. Koster, and R. R. Ruffolo, Jr. 1991. Effect of the dopamine p-hydroxylase inhibitor, SK&F 102698, on blood pressure in the 1-kidney, 1- clip hypertensive dog. Pharmacology 43:90-95.

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