key: cord-341434-2xrdv92m
authors: Nowland, Megan H.; Brammer, David W.; Garcia, Alexis; Rush, Howard G.
title: Biology and Diseases of Rabbits
date: 2015-07-10
journal: Laboratory Animal Medicine
DOI: 10.1016/b978-0-12-409527-4.00010-9
sha: 
doc_id: 341434
cord_uid: 2xrdv92m

Beginning in 1931, an inbred rabbit colony was developed at the Phipps Institute for the Study, Treatment and Prevention of Tuberculosis at the University of Pennsylvania. This colony was used to study natural resistance to infection with tuberculosis (Robertson et al., 1966). Other inbred colonies or well-defined breeding colonies were also developed at the University of Illinois College of Medicine Center for Genetics, the Laboratories of the International Health Division of The Rockefeller Foundation, the University of Utrecht in the Netherlands, and Jackson Laboratories. These colonies were moved or closed in the years to follow. Since 1973, the U.S. Department of Agriculture has reported the total number of certain species of animals used by registered research facilities (1997). In 1973, 447,570 rabbits were used in research. There has been an overall decrease in numbers of rabbits used. This decreasing trend started in the mid-1990s. In 2010, 210,172 rabbits were used in research. Despite the overall drop in the number used in research, the rabbit is still a valuable model and tool for many disciplines.

The rabbit has been utilized in immunology research for many years especially in regard to the structure of immunoglobulins and the genetic control of their formation. In addition, the rabbit is commonly used for the production of polyclonal antibodies for use as immunologic reagents (Mage, 1998; Pinheiro et al., 2011) . The relatively large body size and blood volume, easy access to the vascular system, and an existent large body of information on the purification of rabbit immunoglobulins are a few reasons the rabbit is preferred over other common laboratory animal species for polyclonal antibody production (Stills, 1994) .

The organization of the lymphoid system of the rabbit is comparable to that of other mammals. However, the rabbit does possess two gut-associated lymphoid tissues (GALT) with specialized functions in the maturation of IgM + B cells. These are the vermiform appendix at the distal end of the cecum and the sacculus rotundus at the ileocecal junction (Mage, 1998) .

For many years, the lack of rabbit-specific immunological reagents has limited the study of inflammation and immunity in the rabbit. The use of real-time polymerase chain reaction (RT-PCR) techniques has overcome this limitation and permitted such studies in many species other than man and mice. A quantitative real-time RT-PCR assay for measuring mRNA for rabbit cytokines IFN-γ, IL-2, IL-4, IL-10, and TNF-α has been described (Godornes et al., 2007) . Recently, Schnupf and Sansonetti (2012) reported on RT-PCR primer pairs for analysis of three chemokines and CCL20) and 16 cytokines (IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p35, IL12p40, IL-17A, IL-17F, . The profile of cytokines in the rabbit appears similar to other mammals.

In mice and humans, the primary antibody repertoire is created by combinatorial rearrangement of a large number of immunoglobulin gene segments. Other species (chicken, sheep, cattle, and rabbit) that have a limited number of gene segments utilize somatic gene conversion and/or somatic hypermutation (Pinheiro et al., 2011) . In the former, a portion of the immunoglobulin gene is replaced with a gene sequence from a nonfunctional pseudogene. In the latter, single-nucleotide changes are made in the immunoglobulin genes (Jenne et al., 2003) . In the rabbit, gene diversification occurs initially in the fetus and the neonate in sites such as the bone marrow. Subsequently, between 4 and 8 weeks of age, immature IgM + B cells undergo further diversification in the GALT (appendix, sacculus rotundus, and Peyer's patches) (Mage et al., 2006; Pinheiro et al., 2011) . Furthermore, certain species of intestinal bacteria (Bacteroides fragilis and Bacillus subtilis) are required for appendix follicle development and antibody diversification to occur (Hanson and Lanning, 2008; Mage et al., 2006) .

Most mammals express five classes of immunoglobulins: IgM, IgD, IgG, IgA, and IgE. However, the rabbit lacks IgD (Sun et al., 2013) .

The area of cardiovascular research has used the rabbit in a variety of different models. Numerous dietary modifications will induce or exacerbate cholesterolinduced atherosclerosis in the rabbit. A brief overview of some of these dietary modifications can be found elsewhere (Jayo et al., 1994) . Research efforts into cholesterol metabolism have used the Watanabe heritable hyperlipidemic (WHHL) (Atkinson et al., 1992; Kita et al., 1981) and the St. Thomas Hospital strain rabbits (Laville et al., 1987) . The WHHL rabbit has a marked deficiency of low-density lipoprotein (LDL) receptors in the liver and other tissues. Selective breeding of the WHHL rabbit will increase the incidence of coronary artery atherosclerosis without increasing the incidence of aortic atherosclerosis (Watanabe et al., 1985) . In contrast, the St. Thomas Hospital strain has a normal functioning LDL receptor but still maintains a hypercholesterolemic state (Laville et al., 1987) .

Genetically modified rabbits have been created via both intracytoplasmic injection (Li et al., 2010) and retroviral vectors (Hiripi et al., 2010) . This has resulted in a multitude of new strains to address interesting research questions. Cardiovascular disease (Lombardi et al., 2009; Peng, 2012; Sanbe et al., 2005; Stanley et al., 2011) including models of long QT interval for exploration of treatments (Biermann et al., 2011; Jindal et al., 2012; Liu et al., 2012a; Peng, 2012; Sanbe et al., 2005; Ziv et al., 2009 ) and atherosclerosis (Araki et al., 2000; Masson et al., 2011; Tjwa et al., 2006) are the main focus of model development. Strains have also been developed that express human recombinant proteins in rabbit milk (Chrenek et al., 2007; Dragin et al., 2005; Hiripi et al., 2010; Houser et al., 2010; Lipinski et al., 2012; Simon et al., 2011; Soler et al., 2005) . This ability can be passed down for multiple generations (Chrenek et al., 2007; Dragin et al., 2005) .

These human proteins have resulted in antigen production for rotavirus vaccine creation, human factor VIII that could be used to treat hemophilia (Chrenek et al., 2007; Krylov et al., 2008; Simon et al., 2011) and human growth hormone that could supplement a deficiency in that hormone (Lipinski et al., 2012) . Rabbits that express enhanced green fluorescent protein (EGFP) in various tissues have been created for the purpose tracking cells, which is important for tissue engineering and regenerative medicine studies Takahashi et al., 2007; Yin et al., 2013) .

The mouth of the rabbit is relatively small, and the oral cavity and pharynx are long and narrow. The dental formula is i2/1, c0/0, pm3/2, m2-3/3 × 2 = 26 or 28 teeth.

A small pair of incisors is present directly caudal to the primary maxillary incisors and is referred to as 'peg' teeth. The peg teeth are used along with the primary incisors to bite and shear food. The absence of second incisors has been noted in some rabbit colonies as a dominant trait (I 2 /I 2 or I 2 /i 2 ). The teeth of rabbits erupt continuously throughout life and therefore will continue to grow unless normal occlusion and use are sufficient to wear teeth to a normal length. Molars do not have roots and are characterized by deep enamel folds. Rabbits normally masticate with a chewing motion that facilitates grinding of food by movement of the premolars and molars from side to side and front to back.

The rabbit has four pairs of salivary glands, including the parotid, submaxillary, sublingual, and zygomatic. The parotid is the largest and lies laterally just below the base of the ear. The zygomatic salivary gland does not have a counterpart in humans.

The esophagus of the rabbit has three layers of striated muscle that extend the length of the esophagus down to, and including, the cardia of the stomach. This is in contrast to humans and many other species, which have separate portions of striated and smooth muscle along the length of the esophagus. There are no mucous glands in the esophagus of the rabbit.

Although the stomach of the rabbit holds approximately 15% of the volume of the gastrointestinal tract, it is never entirely empty in the healthy rabbit. The gastric contents often include a large amount of hair ingested as the result of normal grooming activity. The stomach is divided into the cardia, fundus, and pylorus.

The liver has four lobes. The gallbladder is located on the right. From the liver, the common bile duct empties into the duodenum posterior to the pylorus. Rabbits produce relatively large amounts of bile compared to other common species. The pancreas is diffuse within the mesentery of the small intestine and enters the duodenum 30-40 mm distal to the common bile duct.

The small intestine of the rabbit is short relative to that of other species and comprises approximately 12% of the total length of the gastrointestinal (GI) tract. Because the GI tract of the rabbit is relatively impermeable to large molecules, kits receive most of their passive immunity via the yolk sac prior to birth rather than by colostrum. Peyer's patches are found along the ileum, particularly near the cecal junction. The sacculus rotundus is a large bulb of lymphoid tissue located at this junction.

The large intestine includes the cecum, the ascending colon, the transverse colon, and the descending colon. The ileocecal valve regulates flow of chyme into the cecum and retards reverse flow back into the ileum. The cecum is very large with a capacity approximately 10-times that of the stomach. The cecum ends in a blind sac, the appendix.

The colon is divided into proximal and distal portions by the fusus coli, which serves to regulate the elimination of hard versus soft fecal pellets. Hard pellets comprise about two-thirds of the fecal output. Soft pellets, or 'cecotrophs,' have a high moisture content and are rich in nitrogen-containing compounds (Ferrando et al., 1970) and the Β vitamins niacin, riboflavin, pantothenate, and cyanocobalamin. Rabbits consume cecotrophs directly from the anus to obtain significant nutritional benefit. Soft pellets are sometimes termed 'night feces,' since they are generally produced at night in domestic rabbits. In contrast, the circadian rhythm of cecotrophy is reversed in wild rabbits, occurring during the day when the animals are in their burrows (Hornicke, 1977) .

Nostrils of rabbits are well equipped with touch cells, and they have a well-developed sense of smell. Nasal breathing in rabbits is characterized by twitching of the nostrils at rates varying from 20 to 120 times per minute, although twitching may be absent in the relaxed rabbit. It has been speculated that inspiration occurs as the nostril moves up and that this serves to direct the flow of air over the turbinate bones where the olfactory cells are most concentrated.

The musculature of the thoracic wall contributes little to respiratory efforts. Instead, rabbits rely mostly on the activity of the diaphragm. Because of this, artificial respiration is easily performed by alternating the head of the rabbit between the up and down positions, 30-45 times per minute, while holding the animal. Compression and release of the chest wall is an ineffective means of artificial respiration in the rabbit.

The pharynx of the rabbit is long and narrow, and the tongue is relatively large. These features make endotracheal intubation difficult. The procedure is further LABORATORY ANIMAL MEDICINE complicated by the propensity of the rabbit to laryngospasm during attempts to intubate the trachea.

The rabbit lungs consist of six lobes. Both right and left sides have cranial, middle, and caudal lobes, with the right caudal being further subdivided into lateral and medial portions. Flow volume of air to the left lung is higher than that to the right due to the lower resistance of the proximal airways per unit volume (Yokoyama, 1979) . In rabbits, lung volume increases with age, in contrast to that of humans and dogs, in which it decreases. Bronchial-associated lymphoid tissue (BALT) is present as distinct tissue.

A unique feature of the cardiovascular system of the rabbit is that the tricuspid valve of the heart has only two cusps, rather than three as in many other mammals. A small group of pacemaker cells generate the impulse of the sinoatrial (SA) node in the rabbit, a feature that facilitates precise determination of the location of the pacemaker (Bleeker et al., 1980; Hoffman, 1965; West, 1955) . The SA and atrioventricular (AV) nodes are slender and elongated, and the AV node is separated from the annulus fibrosus by a layer of fat (Truex and Smythe, 1965) .

Additional unique anatomic features of the cardiovascular system of the rabbit have been utilized to advantage. The aortic nerve subserves no known chemoreceptors (Kardon et al., 1974; Stinnett and Sepe, 1979) and responds to baroreceptors only. Because the aortic nerve, which becomes the depressor nerve, runs alongside but separate from the vagosympathetic trunk, it lends itself readily to implantation of electrodes (Karemaker et al., 1980) .

The blood supply to the brain is restricted mainly to the internal carotid artery. Blood supplied via the vertebral arteries is limited. The aorta of the rabbit demonstrates rhythmic contractions that arise from neurogenic stimulation in a pattern related to the pulse wave (Mangel et al., 1981) .

The kidneys of the rabbit are unipapillate in contrast to those of most other mammals, which are multipapillate. This feature increases the ease with which cannulization is performed. The right kidney lies more cranial than the left.

Glomeruli increase in number after birth in rabbits, whereas all of the glomeruli are present at birth in humans (Smith, 1951) . Ectopic glomeruli are normal in the rabbit (Steinhausen et al., 1990) . Blood vessels that perfuse the medulla remain open during many conditions under which vasoconstriction of the cortical tissue occurs; thus, the medullary tissue may be perfused, while the cortex is ischemic (Trueta et al., 1947) .

The urine of adult rabbits is typically cloudy due to a relatively high concentration of ammonium magnesium phosphate and calcium carbonate monohydrate precipitates (Flatt and Carpenter, 1971) . The urine may also take on hues ranging from yellow or reddish to brown. In contrast, the urine of young rabbits is typically clear, although healthy young rabbits may have albuminuria. The urine is normally yellow but can also take on reddish or brown hues once animals begin to eat green feed and cereal grains. Normal rabbits have few cells, bacteria, or casts in their urine. The pH of the urine is typically alkaline at about 8.2 (Williams, 1976) . A normal adult rabbit produces approximately 50-75 ml/kg of urine daily (Gillett, 1994) , with does urinating more copiously than bucks.

The urethral orifice of the buck is rounded, whereas that of the doe is slit-like. This feature is useful for distinguishing the sexes. The testes of the adult male usually lie within the scrotum; however, the inguinal canals that connect the abdominal cavity to the inguinal pouches do not close in the rabbit. For this reason, the testes can easily pass between the scrotum and the abdominal cavity. This feature necessitates closure of the superficial inguinal ring following orchiectomy by open technique to prevent herniation.

The reproductive tract of the doe is characterized by two uterine horns that are connected to the vagina by separate cervices (bicornuate uterus). A common tube, the urogenital sinus or vestibulum, is present where the urethra enters the vagina. The placenta is hemochorial, and maternal blood flows into sinus-like spaces where the transfer of nutrients and other substances to the fetal circulation occurs (Jones and Hunt, 1983) .

Inguinal pouches are located lateral to the genitalia in both sexes. The pouches are blind and contain scent glands that produce white to brown secretions that may accumulate in the pouch.

The metabolic rate of endotherms is generally related to the body surface area. Including the ears, the rabbit has a relatively low metabolic rate (MR); however, if the surface area of the ears is discounted, the MR of the rabbit is similar to that of other endotherms.

Neonatal rabbits have an amount of body fat comparable to that of the human infant (16% of body weight) (Cornblath and Schwartz, 1976) . The neonatal rabbit is essentially an ectotherm until about day 7 (Gelineo, 1964) . The glucose reserves of the neonatal rabbit are quickly depleted, usually within about 6 h after birth (Shelley, 1961) . The fasting neonatal rabbit quickly becomes hypoglycemic and ketotic (Callikan and Girard, 1979) .

The normal rectal temperature of the adult New Zealand White rabbit at rest is approximately 38.5-39.5°C (Ruckebusch et al., 1991) . The ears serve an important thermoregulatory function. Because they have a large surface area and are highly vascular with an extensive arteriovenous anastomotic system, the ears help the rabbit sense LABORATORY ANIMAL MEDICINE and respond to cold versus warm temperatures (Kluger et al., 1972) . In addition, the ears serve as a countercurrent heat-exchange system to help adjust body temperature.

Early studies found that the body of the adult rabbit (3 kg body weight) consists of greater than 50% water (58%), with a half-time turnover of about 3.9 days and a loss of about 340 ml daily (Richmond et al., 1962) . The amount of water ingested varies with the amount and type of feed consumed and the environmental temperature. In general, rabbits will drink more water when consuming dry, pelleted feed than when consuming foodstuffs high in moisture, such as fresh greens. Conversely, rabbits deprived of water will decrease food consumption. After 3 days of complete water deprivation, food intake falls to less than 2% of normal (Cizek, 1961) .

Normal values for various systems and parameters are provided as a general indication for these values in the rabbit. It is important to recognize, however, that most of these values have been obtained through the study of adult New Zealand White rabbits. As with any experiment, values can vary significantly between breeds, laboratories, methods of sampling and measurement, and individual rabbits due to age, sex, breed, health, handling, and husbandry (Hewitt et al., 1989; Lidena and Trautschold, 1986; Mitruka and Rawnsley, 1981; Wolford et al., 1986; Yu et al., 1979) . For this reason, individual laboratories should strive to establish their own normal values, whenever possible.

Values for hematologic parameters are shown in Table 10 .2. These values represent those typical of adult New Zealand White rabbits. In general, males have slightly greater hematocrit and hemoglobin values than females (Mitruka and Rawnsley, 1981) .

Anisocytosis is normal and accounts for variation in reported values for red blood cell diameter (Sanderson and Phillips, 1981) . Reticulocyte values are usually between 2% and 4% in healthy rabbits (Corash et al., 1988) . The neutrophil of the rabbit is sometimes referred to as a 'pseudoeosinophil' or 'heterophil,' due to the presence of red-staining granules in the cytoplasm. The heterophil (10-15 mm in diameter) is, however, smaller than the eosinophil (12-16 mm in diameter) (Sanderson and Phillips, 1981) . In addition, the red granules of the heterophil are smaller than the red granules of the eosinophil. The nucleus of the eosinophil may be either bilobed or horseshoe-shaped.

As mentioned earlier, chemistry values can vary because of a number of factors. For this reason, each laboratory should establish its own normal values.

Aspartate aminotransferase (AST) is present in the liver, heart, skeletal muscle, kidney, and pancreas. Collection of blood samples in rabbits by decapitation, cardiac puncture, or aortic incision, or the use of restraint that causes exertion will elevate AST levels due to muscle damage (Lidena and Trautschold, 1986) . Similarly, levels of creatinine kinase are sensitive to muscle damage since that enzyme is present in the skeletal muscle, brain, and heart (Lidena and Trautschold, 1986; Mitruka and Rawnsley, 1981) .

Although most mammals have two isoenzymes (intestinal and a liver/kidney/bone form) of alkaline phosphatase (AP), rabbits are unique in having three forms of AP, including an intestinal form and two forms that are both present in the liver and the kidney (Noguchi and Yamashita, 1987) .

Values for blood and serum chemistry are shown in Table 10 .3.

Cardiovascular and respiratory functions are often altered with experimental manipulation, anesthesia, or disease. Normal values for these parameters and other miscellaneous biologic characteristics of the rabbit are listed in Table 10 .4. Values obtained from the following sources: Burns and DeLannoy (1966) , Gillett (1994) , Kabata et al. (1991) , Mitruka and Rawnsley (1981), and Woolford et al. (1986) .

LABORATORY ANIMAL MEDICINE

Rabbits are strictly herbivorous with a preferred diet of herbage that is low in fiber and high in protein and soluble carbohydrate (Cheeke, 1987; Cheeke, 1994) . Rabbits will generally accept a pelleted feed more readily than one in meal form. When a meal diet is needed, a period of adjustment should be allowed for the rabbits to accommodate to the new diet. Examples of adequate diets are shown in Table 10 .5.

The requirement for fiber in the diet of rabbits has been reviewed (Gidenne, 2003) . Fiber is especially important in the early postweaning period when low fiber intake is associated with an increase in digestive disorders (Gidenne, 2003) .

The exact nutrient requirements for individual rabbits vary with age, reproductive status, and health of the animal. On occasion, the need arises for use of highly purified diets. A suggested purified diet has been described elsewhere (Subcommittee on Rabbit Nutrition, 1977) . It should be noted that overfeeding of Values obtained from the following sources: Burns and DeLannoy (1966) , Fox (1989) , Gillett (1994) , Kraus et al. (1984), and Loeb and Quimby (1989) . Values obtained from the following sources: Barzago et al. (1992) , Curiel et al. (1982) , Gillett (1994) , Kozma et al. (1974) , Sanford and Colby (1980) , Suckow and Douglas (1997), and Zurovsky et al. (1995) .

LABORATORY ANIMAL MEDICINE laboratory rabbits resulting in obesity is common, but can be prevented by either reducing the amount of feed or by providing a low-energy, high-fiber maintenance diet (Donnelly, 2004) . As mentioned earlier, rabbits engage in cecotrophy, and by doing so supplement their supply of protein and Β vitamins (Carabaño et al., 2010; Gidenne et al., 2010) . Rabbits fed a diet high in fiber ingest a greater quantity of cecotropes than those on a lower fiber diet (Fekete and Bokori, 1985) .

Unlike most other species, both calcium absorption in the small intestine and serum calcium levels increase in proportion to the amount of calcium in the diet (Cheeke, 1987) . Prolonged feeding of diets high in calcium, such as those with a high level of alfalfa meal, can result in renal disease. Consumption of diets containing excessive vitamin D can result in calcification of soft tissues, including the liver, kidney, vasculature, and muscles (Besch-Williford et al., 1985; Lebas, 2000) .

Diets that are either too high or too low in vitamin A can result in reproductive dysfunction and congenital hydrocephalus (Cheeke, 1987; DiGiacomo et al., 1992) . The exact requirement for vitamin A in the rabbit has not been determined; however, a level of 6000-10,000 IU/kg of diet is generally adequate (Lebas, 2000) .

Vitamin E deficiency has been associated with infertility, muscular dystrophy, fetal death, neonatal death, and colobomatous microphthalmos in rabbits (Lebas, 2000; Nielsen and Carlton, 1995; Ringler and Abrams, 1970; Ringler and Abrams, 1971) . McDowell (1989) suggested that serum vitamin E levels of less than 0.5 μg/ml are indicative of hypovitaminosis E.

Relative to other species, rabbits have a high water intake. In general, daily water intake is approximately 120 ml/kg of body weight. Consumption of water is influenced by environmental temperature, disease states, and feed composition and intake (Cizek, 1961; Tschudin et al., 2011) . Consumption of diets high in dry matter results in increased water intake (Tschudin et al., 2011) . Water consumption also increases with food deprivation.

Rabbits are social animals and attempts at group housing often meet with success, although mature males will fight and can inflict serious injury on one another (Love, 1994; Podberscek et al., 1991; Whary et al., 1993) . Group-penned female rabbits allowed to choose between single or paired housing prefer being in the same cage with other rabbits (Huls et al., 1991) . In general, rabbits are timid and nonaggressive. Some animals will display defensive behavior, typically characterized by thumping the cage floor with the rear feet, biting, and charging toward the front of the cage when opened. Laboratory-housed rabbits demonstrate diurnal behavior, in contrast to the nocturnal pattern exhibited by wild rabbits (Jilge, 1991) .

The ethogram of the laboratory rabbit has been described (Chu et al., 2004; Gunn and Morton, 1995) . The most common behaviors of individually housed rabbits included lie alert, doze, groom, sleep, and eat. Individually housed rabbits were inactive the majority of the time (Gunn and Morton, 1995) . Individually housed female rabbits showed an increase in abnormal behaviors compared to pair-housed rabbits (Chu et al., 2004) . Rabbits housed in pairs in double-wide cages locomoted more than individually housed rabbits (Chu et al., 2004 ).

The age of puberty varies with the breed of rabbit. Puberty generally occurs at 4-5 months of age in small breeds, 4-6 months in medium breeds, and 5-8 months in large breeds (Donnelly, 2004) . Female New Zealand White rabbits reach maturity at 5 months of age and males at 6-7 months. 

The breeding life of a doe typically lasts approximately 1-3 years, although some remain productive for up to 5 or 6 years. In later years, litter sizes usually diminish. In comparison, most bucks will remain reproductively useful for an average of 5-6 years.

Because does often will engage in reproductive behavior before being able to ovulate, it is advisable not to breed does until they are fully grown.

Does do not have a distinct estrous cycle, but rather demonstrate a rhythm with respect to receptivity to the buck. Receptivity is punctuated by periods (1-2 days every 4-17 days) of anestrus and seasonal variations in reproductive performance (Hafez, 1970) . During periods of receptivity, the vulva of the doe usually becomes swollen, moist, and dark pink or red. Receptivity of the doe is usually signaled by lordosis in response to the buck's attempt to mount, vulvar changes as described above, restlessness, and rubbing of the chin on the hutch or cage (Donnelly, 2004) . Vaginal cytology is generally not useful for determination of estrus or receptivity in the rabbit.

Typically, the doe is brought to the buck's cage for breeding, since the doe can be very territorial and may attack the male in her own quarters. A period of 15-20 min is usually sufficient to determine compatibility of the doe and buck. If receptive, the doe will lie in the mating position and raise her hindquarters to allow copulation. If fighting or lack of breeding is observed, the doe may be tried with another buck. A single buck is usually sufficient to service 10-15 does.

Ovulation is induced and occurs approximately 10-13 h after copulation (Donnelly, 2004) . Up to 25% of does fail to ovulate following copulation. Ovulation can also be induced by administration of luteinizing hormone (Kennelly and Foote, 1965) , human chorionic gonadotropin (Williams et al., 1991) , or gonadotropic releasing hormone (Foote and Simkin, 1993) .

Does may be bred immediately after kindling; however, most breeders delay until after the kits have been weaned. Success at postpartum breeding varies, but one can produce a large number of kits in a relatively short time period by foster nursing the young and rebreeding the doe immediately. While conventional breeding, nursing, and weaning schedules allow for only 4 litters per year, early postpartum breeding allows for up to 11 litters per year.

Pregnancy can often be confirmed as early as day 14 of gestation by palpation of the fetuses within the uterus. Radiographic procedures permit pregnancy determination as early as day 11. Conception rates have been observed to have an inverse relationship with ambient temperature but not light cycle. Gestation in rabbits usually lasts for 30-32 days (Donnelly, 2004) . Does beyond 2-3 weeks of gestation will usually refuse a buck.

Does begin hair pulling and nest building during the last 3-4 days of gestation (Donnelly, 2004) . A nesting box with shredded paper or other soft material such as straw should be provided to the doe several days prior to the expected kindling (parturition) date. The doe will usually line the box with her own hair. The nesting box should not be placed in the corner of the cage where the individual doe has been observed to urinate.

Pseudopregnancy is common in rabbits and can follow a variety of stimuli, including mounting by other does, sterile matings by bucks, administration of luteinizing hormone, or the presence of bucks nearby. In such circumstances, ovulation is followed by a persistent corpus luteum that lasts 15-17 days. The corpus luteum or corpora lutea secretes progesterone during this time, causing the uterus and mammae to enlarge. The doe may have the appearance of a normally pregnant rabbit. Toward the end of pseudopregnancy, many does will begin to pull hair as part of ritual nest-building behavior.

The process of parturition is referred to as 'kindling' when it relates to rabbits. Kindling normally occurs during the early morning hours and takes approximately 30-60 min. Impending kindling is often signaled by nest building and decreased food consumption during the preceding 2-3 days. Both anterior and breech presentations are normal in the rabbit. Fetuses retained beyond 35 days generally die and may harm future reproductive ability of the doe if not expelled.

The average number of kits born is seven to nine per litter, although smaller litters and litters of up to 10 kits are not uncommon. Breed, parity, nutritional status, and environmental factors influence litter size. Polish rabbits usually have fewer than four kits per litter; Dutch or Flemish Giant, four to five; and New Zealand White, eight to ten.

After the young have been cleaned following parturition, the doe typically consumes the placenta. Cannibalism of the young by the doe sometimes occurs and may be related to environmental or hereditary factors or due to environmental stressors.

Does usually have either four or five pairs of nipples, whereas bucks have none. During the last week of pregnancy, marked development of the mammary gland occurs. The doe normally nurses the kits once daily for several minutes, usually in the early morning or in the evening, regardless of how many kits are present or LABORATORY ANIMAL MEDICINE how many times they attempt to suckle. Milk yield is normally between 160 and 220 g/day. During the first week of life, kits consume 15-25 g of milk per day. Milk intake increases gradually to a maximum of 30 g/day between 17 and 25 days of age (Gidenne et al., 2010) . Maximum output occurs at 2 weeks following kindling and then declines during the fourth week. Rabbit milk contains approximately 12.5% protein, 13% fat, 2% lactose, and 2.5% minerals. Nursing may last 5-10 weeks. Kits may begin consuming solid food by 3 weeks of age, with weaning generally occurring by 5-8 weeks of age.

The facilities present in most modern research animal facilities would be suitable for housing rabbits. General construction should include adequate heating, ventilation, and air conditioning to house rabbits at appropriate temperature and humidity. In addition, lighting should be adequate to allow easy visualization of the rabbits. Surfaces, such as the floors, walls, and ceilings, should be easily sanitizable (National Research Council, 2011) .

Rabbit cages should provide a safe environment with easy access to food and water. Adults can be caged individually or in compatible groups and should have sufficient floor space to lie down and stretch out. In the United States, minimum cage sizes are determined by the Animal Welfare Act (AWA) and the Guide for the Care and Use of Laboratory Animals (Guide). In both cases, sizes vary with the weight of the animal. Currently, the AWA regulations and the Guide require 3.0 ft 2 of floor space and 16 in of cage height for rabbits weighing 2-4 kg (National Research Council, 2011) .

Cages should be constructed of durable materials that will resist corrosion and harsh detergents and disinfectants used in cleaning. Consequently, in the research environment, rabbit cages are most often constructed of stainless steel or plastics. Rabbits are usually housed in cages with mesh or slatted floors to permit urine and feces to drop through into a catch pan. Mesh floors with catch pans do not prevent rabbits from engaging in the normal practice of coprophagy.

Information on environmental enrichment of laboratory rabbits has been published (Baumans, 2005) . The behavior of rabbits in conventional cages was compared to that of rabbits provided with enriched cages that contained shelter, a shelf, and increased vertical space. Rabbits in conventional cages were more restless, groomed excessively, exhibited more bar-gnawing, and were more timid than those housed in enriched cages (Hansen and Berthelsen, 2000) . Indeed, fecal glucocorticoid levels in rabbits declined when they were provided with a wooden structure for resting and gnawing (Buijs et al., 2011) . Rabbits will play with objects placed in their cages. Huls et al. (1991) noted that rabbits would use wooden sticks, wooden rings, and brass wire balls as toys. Rabbits provided with objects (toys) spent significantly more time chewing than rabbits without toys (Poggiagliolmi et al., 2011) . Female rabbits can also be housed in compatible pairs or groups. Singly housed female rabbits exhibited more abnormal behaviors compared to pair housed rabbits (Chu et al., 2004) . Group housing of unfamiliar males is not recommended because of the likelihood of fighting and injury.

Rabbits are optimally housed in cooler room temperatures than most other common species of laboratory animals. The Guide recommends that temperatures in rabbit rooms be maintained between 61 and 72°F.

No specific illumination requirements for rabbits have been described. It is common practice to provide rabbits with 12-14 h of light in the light-dark cycle. In breeding colonies, females should be provided with 14-16 h of light.

Rabbits are easily startled by sudden, loud noises. For this reason, they should not be housed near noisy species such as dogs or monkeys, nor should they be housed near noise-generating operations such as the cage-wash area.

Catch pans should be cleaned as often as necessary to prevent the formation of ammonia. Cages are generally sanitized on at least a weekly basis.

Rabbit urine contains large amounts of protein and minerals, and often forms deposits on cages and catch pans. It is common practice to soak equipment having urine deposits in acid washes to remove the scale before washing.

Ammonia production in rabbit rooms can be a significant problem; therefore, rabbit rooms should be ventilated at 10-15 air changes per hour (National Research Council, 2011) . It is also important to change excreta pans often to prevent the buildup of ammonia.

Etiology Pasteurella multocida is a Gram-negative nonmotile coccobacillus that causes pasteurellosis, also known as 'snuffles', the primary respiratory disease affecting domestic rabbits (Deeb and DiGiacomo, 2000; Guo et al., 2012) . Historically, serogroup A isolates have LABORATORY ANIMAL MEDICINE been associated with pneumonic and septicemic pasteurellosis in laboratory rabbits; however, capsular type A is also isolated from rabbits that appear clinically healthy (Confer et al., 2001; El Tayeb et al., 2004) .

Clinical Signs Pasteurella multocida infection is often subclinical, but pasteurellosis may cause fever, coughing, dyspnea, rhinitis (nasal discharge (serous to mucopurulent), sneezing, and upper airway stentor), pneumonia, otitis, septicemia, meningitis, abscesses (of viscera and subcutaneous sites), and death (Al-Lebban et al., 1989; Confer et al., 2001; Franco and Cronin, 2008; Guo et al., 2012; Suckow et al., 2002; Wilkie et al., 2012) . Pasteurellosis may also be associated with pericarditis, pleuritis, sinusitis, dacryocystitis, conjunctivitis, iritis/ uveitis, phlegmon, mastitis, endometritis, pyometra, salpingitis, and orchitis (Deeb and DiGiacomo, 2000; Ferreira et al., 2012; Stahel et al., 2009; Williams, 2012) .

Epizootiology P. multocida can be endemic in rabbitries and is carried in the rabbit's nasal cavity (Confer et al., 2001; Deeb et al., 1990; DiGiacomo et al., 1991; Suckow et al., 2008) . Transmission is by direct contact between rabbits (Wilkie et al., 2012) . Coinfection with Bordetella bronchiseptica may be observed in clinically affected rabbits (Deeb et al., 1990) . Stress-related factors associated with pasteurellosis include crowded or unsanitary conditions, transportation, and high ammonia concentrations in the air (Confer et al., 2001) . Previous studies reported a high prevalence of P. multocida infection (Jaslow et al., 1981) . Colonization in immature rabbits occurs more commonly in the sinuses followed by the trachea, middle ears, and lungs (Glass and Beasley, 1989) . Similar to cats and dogs, rabbits may transmit P. multocida infection to humans (Per et al., 2010; Silberfein et al., 2006) .

A study utilizing repetitive extragenic palindromic PCR (REP-PCR) and sequencing determined that 82% of the isolates were characterized as P. multocida subsp. multocida, 3% as P. multocida subsp. septica, 5% as atypical subspecies of P. multocida, 5% as P. canis, and 5% as an unknown species of the family Pasteurellaceae (Stahel et al., 2009) .

The pathogenesis of P. multocida has been reviewed (Wilkie et al., 2012) . The ptfA gene, encoding a type 4 fimbrial subunit and involved in bacterial fixation on the surface of epithelial cells, may be highly prevalent in P. multocida isolates from rabbits (Ferreira et al., 2012) . The P. multocida toxin is a major virulence factor in atrophic rhinitis of rabbits and acts by causing constitutive activation of G proteins Frymus et al., 1991; Orth et al., 2009; Suckow et al., 1991) .

Pathology The specific pathologic findings will vary with the site of infection, but the underlying host response is characterized by acute or chronic suppurative inflammation with the infiltration of large numbers of neutrophils.

Rhinitis and sinusitis are accompanied by a mucopurulent nasal exudate. Neutrophil infiltration of the tissues is extensive. The nasal passages are edematous, inflamed, and congested, and there may be mucosal ulcerations. The turbinate bones may atrophy DiGiacomo et al., 1989) . Purulent conjunctivitis may be present.

Pneumonia is primarily cranioventral in distribution. The lungs can exhibit consolidation, atelectasis, and abscess formation. A purulent to fibrinopurulent exudate is evident, and there may be areas of hemorrhage and necrosis. In some rabbits, fibrinopurulent pleuritis and pericarditis are prominent features (Glavits and Magyar, 1990) . This is probably due to elaboration of a heat-labile toxin in some strains of the bacteria . Acute hepatic necrosis and splenic lymphoid atrophy are also seen in association with the pleuritis and pneumonia induced by toxigenic strains.

Otitis media is characterized by a suppurative exudate with goblet cell proliferation and lymphocytic and plasma cell infiltration.

In female rabbits with genital tract infections, the uterus may be enlarged and dilated. In the early stages of infection, the exudate is watery; later it thickens and is cream-colored. The exudate contains numerous neutrophils. Focal endometrial ulceration can be found (Johnson and Wolf, 1993) . In the male, the testes are enlarged and may contain abscesses.

Systemic and visceral abscesses are characterized by a necrotic center, an infiltrate made up of polymorphonuclear neutrophils, and a fibrous capsule.

Septicemia may only present as congestion and petechial hemorrhages in many organs.

Severe pleuritis with accumulation of fibrinopurulent exudate in the thoracic cavity, serous rhinitis and tracheitis, acute hepatitis with necrotic foci in the parenchyma, and atrophy of lymphoid organs and tissues have been observed after experimental P. multocida infection in rabbits (Glavits and Magyar, 1990) .

Diagnosis Sterile swabs can be used to collect samples from the nares or nasal cavity of rabbits for culture (Ferreira et al., 2012; Jaslow et al., 1981) . Nasal lavage can also be used as a culture sample to isolate Pasteurella (Suckow et al., 2002) . P. multocida isolates can be classified into five serogroups based on capsular antigens (A, B, D, E, and F) and into 16 serotypes based on somatic LPS antigens (Adler et al., 1999; Liu et al., 2012b; Manning, 1982) . Biochemical characterization of isolates may show high heterogeneity; however, REP-PCR and phylogenetic analysis using 16S ribosomal RNA and rpoB genes can be used for precise characterization of rabbit isolates (Stahel et al., 2009) . Classification of P. multocida into subspecies and/or by virulence profiles is useful for epidemiological investigations (Ferreira et al., 2012; Stahel et al., 2009) . Random amplified polymorphic LABORATORY ANIMAL MEDICINE DNA PCR (RAPD-PCR) has also been used to subtype rabbit P. multocida isolates (Al-Haddawi et al., 1999; Dabo et al., 2000; Williams et al., 1990) . PCR can detect capsule biosynthesis genes cap A, B, D, E, and F as well as virulence-related genes (Ferreira et al., 2012) . Serological tests can be used to detect antibodies against P. multocida (Deeb et al., 1990; Delong et al., 1992; DiGiacomo et al., 1990; Glass and Beasley, 1989; Lukas et al., 1987) .

Differential Diagnoses If radiographs reveal an internal mass associated with P. multocida infection, the differential diagnoses should include abscess, granuloma, neoplasia, and parasitic cyst (Franco and Cronin, 2008) .

Treatment, Prevention, and Control Previous studies have investigated the use of vaccines to protect rabbits against P. multocida infection (Confer et al., 2001) . Immunization of rabbits with inactivated heat-labile P. multocida toxin or a commercial swine P. multocida bacterin-toxoid conferred protective immunity against challenge with the P. multocida heat-labile toxin (Suckow, 2000; Suckow et al., 1995) . A vaccine administered intranasally stimulated immunity against experimental pneumonic pasteurellosis and significantly reduced nasal bacterial counts (Confer et al., 2001) . Oral immunization of rabbits with a P. multocida thiocyanate extract (PTE) in microparticles was immunogenic and significantly reduced the colony-forming units of homologous P. multocida recovered from the lungs and nasopharynx (Suckow et al., 2002) . Protective immunity to a heterologous strain of P. multocida can be achieved by vaccinating rabbits with PTE via the subcutaneous route (Suckow et al., 2008) . A P. multocida bacterin known as BunnyVac is currently licensed by the USDA and is intended to be effective in preventing death and limiting disease due to Pasteurella in rabbits. BunnyVac is manufactured by Colorado Serum Company and distributed by Pan American Veterinary Laboratories (http://pavlab. com/). Control of pasteurellosis in rabbitries entails testing and culling animals that are positive for Pasteurella spp. (Ferreira et al., 2012) . Furthermore, rabbits free of Pasteurella and other infectious agents can be obtained by enrofloxacin treatment and through cesarean section or hysterectomy rederivation (Pleasants, 1959; Suckow et al., 1996; Syukuda, 1979) . Commercial suppliers of laboratory rabbits tend to exclude Pasteurella from their colonies.

Treatment with antibiotics should be based on culture and sensitivity. Antibiotic treatment of affected rabbits can alleviate clinical signs or delay disease progression but may not eradicate the disease (El Tayeb et al., 2004; Ferreira et al., 2012) . Antibiotic treatment may suppress virulence gene expression without complete elimination of P. multocida . Internal abscesses may not be treatable using antibiotics (Franco and Cronin, 2008) . Penicillin therapy does not seem to be effective against Pasteurella infection and may also lead to diarrhea and Clostridium difficile colitis in rabbits (Jaslow et al., 1981; Rehg and Lu, 1981) . One study from Brazil determined that all tested strains were sensitive to ceftiofur, florfenicol, norfloxacin, enrofloxacin, ciprofloxacin, tetracycline, and doxycycline (Ferreira et al., 2012) . Other studies also indicate that fluoroquinolones are useful for the treatment of P. multocida infection in rabbits (Abo-El-Sooud and Goudah, 2010; Broome and Brooks, 1991; Franco and Cronin, 2008; Hanan et al., 2000; Okewole and Olubunmi, 2008) . Oral ciprofloxacin (20 mg/kg per day for 5 days) has been used in rabbits (Hanan et al., 2000) .

Research Complications Pasteurellosis can cause considerable economic losses (El Tayeb et al., 2004; Ferreira et al., 2012; Stahel et al., 2009 ) and has the potential to affect different types of research studies using rabbits due to the multisystemic nature of the disease, and the possibility of high morbidity and mortality. Therefore, Pasteurella should be excluded from laboratory rabbit colonies.

The class Clostridia belongs to the phylum Firmicutes (Yutin and Galperin, 2013) . Recent genomic analyses suggest assigning some Clostridium species that fall outside the family Clostridiaceae into new genera. The genera Tyzzerella, Erysipelatoclostridium, and Peptoclostridium have been proposed for C. piliforme, C. spiroforme, and C. difficile, respectively (Yutin and Galperin, 2013) .

Etiology C. piliforme is a pleomorphic, Gramnegative, spore-forming, motile, obligate intracellular rod-shaped bacterium that causes Tyzzer's disease and infects various animals including mice, nonhuman primates, gerbils, rats, rabbits, and others (Allen et al., 1965; Ganaway et al., 1971; Pritt et al., 2010) . Infection has also been reported in a human patient with human immunodeficiency virus-1 (Smith et al., 1996) . Phylogenetic analyses determined that microorganisms identified as C. piliforme form three clusters within a single clade and that the nearest related distinguishable species is C. colinum (Feldman et al., 2006) .

Clinical Signs The first reported outbreaks in laboratory rabbits described profuse watery to mucoid diarrhea usually followed by death in 12-48 h in 3-to 8-week old rabbits (Allen et al., 1965) . Rabbits in affected litters usually died within a week after the first fatality (Allen et al., 1965) . The dams of affected litters occasionally died after a diarrheal disease that was more protracted than that of the offspring (Allen et al., 1965) . These outbreaks lasted for 6-8 months and affected multiple rabbit rooms. C. piliforme infection may also be subclinical and transient as immunocompetent hosts may clear the infection (Ganaway et al., 1971; Pritt et al., 2010) . Weanling rabbits with the acute form of Tyzzer's disease exhibit diarrhea, listlessness, anorexia, and dehydration usually followed by death within 72 h (Cutlip et al., 1971) . The mortality rate in clinically affected rabbits was estimated to be 90-95% (Cutlip et al., 1971) . Anorexia and stunting were observed in chronic cases associated with intestinal stenosis (Cutlip et al., 1971) . Acute and chronic Tyzzer's disease types have been described in rabbits; however, large numbers of 'attaching' Escherichia coli were recovered from the cecum of most rabbits (Prescott, 1977) .

Epizootiology The vegetative cell is the active stage responsible for the disease and depends on the intracellular environment (Ganaway, 1980) . Therefore, the spore, a resistant stage, appears to be the essential element in the transmission of Tyzzer's disease (Ganaway, 1980; Ganaway et al., 1971) . Contact with soiled bedding or diseased rabbits have been used experimentally to transmit the disease to other rabbits (Allen et al., 1965) . It is possible that subclinically infected rabbits (carriers) may introduce the organism into a colony (Allen et al., 1965; Pritt et al., 2010) . In mice, increased susceptibility to infection has been associated with stress (Allen et al., 1965) . Furthermore, treatment with cyclophosphamide, cortisone, and prednisolone has been used experimentally to reproduce the disease in animals, suggesting that immunosuppression plays a role in pathogenesis (Allen et al., 1965; Cutlip et al., 1971; Pritt et al., 2010) . Animals stressed by poor environmental conditions including overcrowding and extreme temperatures can develop the disease (Cutlip et al., 1971; Wobeser et al., 2009 ). Significant modifications of the intestinal flora and an impaired immune system may play a role in pathogenesis (Licois, 1986) . C. piliforme may be transported from the intestine to the liver through the portal circulation and to the heart through the lymphatics (Allen et al., 1965) . Some C. piliforme isolates can induce cytopathic effects on cell cultures, and in vivo, concomitant infection with other enteric pathogens such as E. coli may contribute to the severity of the disease (Prescott, 1977; Riley et al., 1992) .

Pathology Lesions can be found in the distal ileum, cecum, proximal colon, liver, and heart (Allen et al., 1965) . Intestinal lesions are common, and histologically are characterized by necrosis of the mucosa and edema of the submucosa and serosa (Allen et al., 1965) . Bacilli appear as bundles of parallel rods or as criss crossed sticks in the cytoplasm of epithelial cells distributed from the surface of the mucosa to the base of the glands (Allen et al., 1965) . The lesions in the liver are punctate areas of parenchymal necrosis that appear grossly as white spots, usually ≤ 2 mm in diameter. Large numbers of bacilli are found in the cytoplasm of cells in the zone of transition between the necrotic lesion and the healthy parenchyma (Allen et al., 1965) . Myocardial lesions appear as white streaks 0.5-2 mm wide and 4-8 mm long extending from the region of the left interventricular groove laterally across the left ventricle (Allen et al., 1965) . In the myocardium, bacilli may be noted in partially degenerated and normal looking cells at the sharply delineated borders of the lesions (Allen et al., 1965) .

Diagnosis C. piliforme cannot be cultured in artificial (cell-free) media making its diagnosis difficult (Allen et al., 1965; Cutlip et al., 1971; Ganaway et al., 1971; Niepceron and Licois, 2010) . Other bacteria, including E. coli, have been isolated from the liver of diseased rabbits and are considered secondary invaders (Allen et al., 1965; Cutlip et al., 1971) . The isolation of the Tyzzer's agent using liver extract agar has been described (Kanazawa and Imai, 1959) . C. piliforme can be grown in primary monolayer cultures of adult mouse hepatocytes, in mouse fibroblasts, in rat hepatocytes, and in embryonated eggs (Craigie, 1966; Duncan et al., 1993; Ganaway et al., 1971; Kawamura et al., 1983; Pritt et al., 2010; Riley et al., 1992) .

Serology for C. piliforme is commonly used for surveillance of laboratory animals because it is rapid and inexpensive (Pritt et al., 2010) . Immunofluorescence assay (IFA) and multiplexed fluorometric immunoassay (MFIA) have been utilized (Pritt et al., 2010) . In addition, C. piliforme PCR assays have been developed (Feldman et al., 2006; Gao et al., 2012; Niepceron and Licois, 2010; Pritt et al., 2010) . Clostridium piliforme seropositive rabbits may be negative for the organism by PCR and histopathological evaluation (Pritt et al., 2010) . Therefore, positive serological findings are not sufficient for a definitive diagnosis of C. piliforme infection and PCR testing and/or histopathology should be used for confirmation (Pritt et al., 2010) .

Definitive diagnosis is based on identification of typical gross lesions and histological demonstration of intracellular C. piliforme at the periphery of the necrotic foci (Niepceron and Licois, 2010; Pritt et al., 2010) . Giemsa solution (pH 4), Warthin-Starry silver method, Levaditi silver method, and the periodic acid-Schiff (PAS) reaction have been used to demonstrate C. piliforme (Allen et al., 1965; Cutlip et al., 1971) . Different morphologic forms of C. piliforme can be observed microscopically (Allen et al., 1965; Ganaway et al., 1971) .

Differential Diagnoses Clinically, other diarrheal diseases of rabbits can be included in the differential diagnoses. Grossly, the multifocal white areas on the liver could be from Eimeria stiedae infection (hepatic coccidiosis).

Treatment, Prevention, and Control For prevention, avoid introduction of rabbits of unknown C. piliforme status into a colony. Minimize stress-related factors especially in young animals. Good husbandry practices including regular bedding changes and disinfection LABORATORY ANIMAL MEDICINE should decrease the likelihood of spreading C. piliforme in a colony.

In one report, a Tyzzer's disease outbreak was observed 7-10 days after rabbits were weaned and transferred to a facility in which the temperature fluctuated from 6 to 35°C. The outbreak was controlled by transferring weanling rabbits to a building maintained at the same temperature as the breeder house (22-26°C) (Cutlip et al., 1971) . Spores treated with heat (70 or 80°C) or with either peracetic acid (1%) in a wetting agent (sodium alkylarylsulfonate) or sodium hypochlorite solution (0.3%) for 5 min lose infectivity (Ganaway, 1980) . However, spores do not lose infectivity when treated with a phenolic germicidal agent, ethanol, or quaternary ammonium compounds (containing 9% or 17% benzalkonium chloride) (Ganaway, 1980) . Sodium hypochlorite solution (0.3%) has been recommended as a surface disinfectant in animal facilities for prevention and control of Tyzzer's disease (Ganaway, 1980) .

The sensitivity of C. piliforme to antibiotics has been investigated (Kanazawa and Imai, 1959) . In one study, none of the antibacterials tested were completely inhibitory (Ganaway et al., 1971) . Group treatment of rabbits with tetracyclines in the drinking water and food was effective in lowering the incidence of diarrhea and death (Prescott, 1977) .

Research Complications The high morbidity and mortality associated with Tyzzer's disease can affect the overall population of rabbits in a colony thereby decreasing the number of rabbits suitable or available for experimentation. In addition, research studies involving experimental infection with enteric pathogens in rabbits may be confounded by C. piliforme-associated intestinal pathology.

Enterotoxemia refers to conditions of the bowel caused by toxigenic clostridia (Carman and Evans, 1984) . Diagnosis of enterotoxemia should be based on culture of a toxigenic clostridium and demonstration of the toxin from the intestinal contents of the diseased animal (Carman and Evans, 1984; Songer, 1996) .

i. CLOSTRIDIUM SPIROFORME Etiology C. spiroforme is a Gram-positive, sporebearing, helically coiled, semicircular, anaerobic bacterium that can produce iota toxin (Borriello and Carmen, 1983; Carman and Borriello, 1984; Peeters et al., 1986) . The disease caused by C. spiroforme is known as 'iota enterotoxemia' (Keel and Songer, 2006; Peeters et al., 1986) .

Clinical Signs Diarrhea, fecal soiling of the perineum, and cyanosis may be observed (Carman and Borriello, 1984) . Diarrhea may be peracute and may lead to 'spontaneous' death or a moribund state (Carman and Borriello, 1984) .

Epizootiology C. spiroforme is thought to be acquired from the environment (Carman and Evans, 1984; Songer, 1996) . Weaning is associated with spontaneous disease and administration of antibiotics can also induce the disease (Borriello and Carmen, 1983; Carman and Borriello, 1984) . A study determined that disease results from exposure of weanling rabbits to C. spiroforme and also from exposure of adult rabbits with a disrupted gut flora (due to clindamycin treatment) to C. spiroforme suggesting that this bacterium is not a normal component of the rabbit gut flora (Carman and Borriello, 1984) . C. spiroforme-mediated diarrhea may be favored by maldigestion initiated by infectious agents and/or nutritional factors (Peeters et al., 1986) . Other clostridia, E. coli (EPEC), viruses, and parasites, may coinfect rabbits (Peeters et al., 1986) . The iota toxin of C. spiroforme binds the same host cell receptor as the iota toxin of C. perfringens and the binary toxin of C. difficile (Papatheodorou et al., 2012) . Poor hygiene, stress, and diet can influence pathogenesis of the disease (Bain et al., 1998; Songer, 1996) .

Pathology Grossly, ceca may be enlarged with gas, may exhibit serosal hemorrhages, and have liquid contents (Carman and Borriello, 1984) . Cecal contents may be stained with blood (Peeters et al., 1986) . C. spiroforme is mainly associated with lesions in the cecum, but may also involve lesions in the proximal colon and distal ileum (Keel and Songer, 2006) . Mucosal necrosis can be observed microscopically (Keel and Songer, 2006) . The mucosa of the ileum, cecum, and colon may be denuded. Cellular debris, red blood cells, and fibrin may be found in the intestinal lumen. Polymorphonuclear cell infiltration and edema can be found in the lamina propria and submucosa. Epithelial degeneration and dilation were found in the renal tubules of some rabbits (Peeters et al., 1986) .

Diagnosis Gram staining of smears prepared from intestinal contents can be used to detect C. spiroforme (Bain et al., 1998) . Clostridial culture and toxin detection assays have been described (Agnoletti et al., 2009; Bain et al., 1998; Borriello and Carmen, 1983; Peeters et al., 1986) . C. spiroforme can be isolated from the intestinal contents of rabbits by high-speed centrifugation (Holmes et al., 1988) . PCR assays for C. spiroforme and the iota toxin (binary toxin) have been developed (Drigo et al., 2008) .

Differential Diagnoses The differential diagnoses should include other clostridia, E. coli, viruses, and parasites (Peeters et al., 1986) .

Treatment, Prevention, and Control The iota toxin from C. spiroforme is neutralized by serum prepared against the iota toxin of C. perfringens type E (Borriello and Carmen, 1983; Carman and Borriello, 1984; Songer, 1996) . Prevention, via reduction of risk factors and prudent use of antibiotics, is probably more important LABORATORY ANIMAL MEDICINE than treatment (Agnoletti et al., 2009) . Cholestyramine has been used to prevent experimental enterotoxemia induced by clindamycin in rabbits (Lipman et al., 1992) . Fecal flora transplants using nonpathogenic C. spiroforme or C. difficile have been suggested for competitive inhibition of toxigenic strains (Carman and Evans, 1984) . No commercial vaccines are available for rabbits; however, vaccination of weanling rabbits with a toxoid imparted protection to intraperitoneal challenge with iota toxin (Songer, 1996) . Administration of antibiotics and change in diet are usually the treatment for C. spiroforme infections (Songer, 1996) . The antibiotic susceptibility of C. spiroforme has been investigated (Agnoletti et al., 2009; Carman and Wilkins, 1991) . C. spiroforme can have a wide range of resistance to antimicrobial classes used in rabbit therapy (Agnoletti et al., 2009) . Feeding fresh meadow hay has been suggested (Bain et al., 1998) .

Research Complications The mortality due to enterotoxemia caused by C. spiroforme would be disruptive to ongoing studies. No other complications have been reported.

ii. CLOSTRIDIUM DIFFICILE Etiology C. difficile is a Gram-positive, sporeforming, anaerobic bacillus commonly associated with diarrhea and colitis in humans and animals (Keel and Songer, 2006) .

Clinical Signs C. difficile infection may be associated with anorexia, depression, diarrhea, fecal-staining of the perineum, decreased fecal output, abdominal distention, and death (Perkins et al., 1995; Rehg and Lu, 1981) . Peracute death, without clinical signs, is also a common presentation in rabbits (Keel and Songer, 2006; Perkins et al., 1995) .

Epizootiology The spread of C. difficile involves carrier animals that do not show clinical signs of disease (Keel and Songer, 2006) . The carrier state may depend on the age of the individual (Keel and Songer, 2006) . C. difficile is thought to be acquired from the environment due to persistent contamination with spores (Keel and Songer, 2006) .

Disease is associated with antibiotic treatment but can also develop spontaneously (without antibiotic treatment) (Perkins et al., 1995; Rehg and Lu, 1981) . The disease may also occur after stressful events such as weaning, sudden dietary changes, lactation, kindling, and illness (Perkins et al., 1995) . Rabbits that have been recently weaned are the most susceptible (Perkins et al., 1995) . Newborn rabbits are resistant to C. difficile disease possibly due to the lack of receptors for the toxins (Keel and Songer, 2006) . Similar to C. spiroforme, the pathogenesis is associated with disruption of the gut flora and with colonization and proliferation of toxigenic Clostridium.

Pathology Grossly, a fluid-filled cecum and colon may be found on necropsy (Rehg and Lu, 1981) . Spontaneous disease in rabbits is associated with lesions in the small intestine, most commonly in the ileum (Keel and Songer, 2006) . In one study, the small intestine was distended with fluid and the cecum was distended with chyme (Perkins et al., 1995) . C. difficile is also associated with hemorrhagic typhlitis in hares (Dabard et al., 1979) .

C. difficile causes severe jejunal lesions in rabbits, but cecal lesions may occur (Keel and Songer, 2006; Perkins et al., 1995) . Mural hemorrhages, mucosal necrosis, and submucosal edema have been observed (Perkins et al., 1995) . Toxins A (enterotoxin) and B (cytotoxin) act synergistically and are essential virulence factors of C. difficile that enter the cells through receptor-mediated endocytosis (Keel and Songer, 2006) . Toxins A and B disrupt the actin cytoskeleton by disrupting Rho-subtype intracellular signaling molecules that affect cellular function (Keel and Songer, 2006) . Inflammation and neurogenic stimuli also are involved in the pathogenesis of C. difficile disease (Keel and Songer, 2006) . In addition to toxins A and B, some C. difficile strains produce an actinspecific ADP-ribosyltransferase or binary toxin (Stubbs et al., 2000) .

Diagnosis C. difficile isolation and toxin assays have been described (Keel and Songer, 2006; Perkins et al., 1995; Rehg and Lu, 1981) . C. difficile selective agar is commercially available. The tissue culture cytotoxin assay for C. difficile toxin B is considered the 'gold standard' (Belanger et al., 2003) . C. difficile toxin B can be neutralized with C. sordelli antiserum, but not with C. spiroforme antiserum (Perkins et al., 1995) . Commercially available enzyme immunoassays to detect C. difficile toxin(s) have been used to diagnose rabbit cases (Garcia et al., 2002; Perkins et al., 1995) . PCR assays have been developed (Belanger et al., 2003; Goldenberg et al., 2010; Houser et al., 2010; Pallis et al., 2013) . Differential Diagnoses The differential diagnosis of peracute death in rabbits should include infection with Clostridium spp. and/or EHEC infection (Garcia et al., 2002; Perkins et al., 1995) .

Treatment, Prevention, and Control As with C. spiroforme, the reduction of risk factors and the prudent use of antibiotics are recommended (Agnoletti et al., 2009) . Cholestyramine may also be used for prevention (Lipman et al., 1992) . Fecal flora transplants have been suggested and commercial probiotic strains are able to inhibit C. difficile and C. perfringens in vitro (Carman and Evans, 1984; Schoster et al., 2013) .

Research Complications The sporadic nature of deaths due to C. difficile infection is unlikely to result in significant complications to research.

iii. CLOSTRIDIUM PERFRINGENS C. perfringens type E produces alpha and iota toxins and is an LABORATORY ANIMAL MEDICINE uncommon cause of enterotoxemia in rabbits (Redondo et al., 2013; Songer, 1996) . Because of the similarity between the iota toxins of C. spiroforme and C. perfringens type E, detection of toxin alone for diagnostic purposes will not differentiate between the two organisms (Songer, 1996) . PCR can be used for typing C. perfringens based on amplification of toxin genes (Daube et al., 1994) .

Historically, a disease process associated with E. coli infection was known as colibacillosis. Currently, E. coli is classified based on the virulence factors that are genetically encoded and expressed in the bacteria. Different virulence factors are associated with different E. coli 'pathotypes'. Pathotypes may be associated with three general clinical syndromes: enteric/diarrheal disease, urinary tract infections, and sepsis/meningitis (Kaper et al., 2004) . The Centers for Disease Control and Prevention currently recognizes six pathotypes associated with diarrhea in humans: enteropathogenic E. coli (EPEC), Shiga toxin (Stx)-producing E. coli (STEC; also known as enterohemorrhagic E. coli (EHEC) or verocytotoxin-producing E. coli (VTEC)), enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC), enteroinvasive E. coli (EIEC), and diffusely adherent E. coli (DAEC) (http://www.cdc.gov/ecoli/general/). Comparative genomic analyses identified genes that were isolateand pathovar-specific and clustered strains according to pathotypes (Lukjancenko et al., 2010; Rasko et al., 2008) . Two more emerging pathotypes have been suggested: adherent invasive E. coli (AIEC; associated with Crohn's disease in humans) and Shiga toxin-producing enteroaggregative E. coli (STEAEC; associated with a large outbreak of hemolytic uremic syndrome (HUS) in Europe) (Clements et al., 2012) . Of these pathotypes, EPEC and STEC are associated with natural disease in rabbits (Cantey and Blake, 1977; Garcia et al., 2002) . In addition, necrotoxigenic E. coli (NTEC) are associated with disease in rabbits (Blanco et al., 1996) . Pathogenic animal and human strains are very closely related and have virulence genes in common (Clermont et al., 2011) . Therefore, it is important to determine which E. coli pathotype(s) are associated with disease in rabbits in order to characterize new diseases and/or more accurately diagnose, prevent, control, and treat the condition as well as for epidemiological investigations.

Etiology EPEC carry the eae gene that encodes intimin, a protein involved in induction of attaching and effacing lesions in the intestine. E. coli serotype O15, also known as RDEC-1, is the prototype EPEC strain which was isolated from rabbits with diarrhea and has been used experimentally as a model to study EPEC-induced disease (Cantey and Blake, 1977) . EPEC is an important cause of potentially fatal infant diarrhea in developing countries (Kaper et al., 2004; Swennes et al., 2012) .

Clinical Signs EHEC O153 was isolated from an outbreak of bloody diarrhea and sudden death in Dutch Belted rabbits (Fig. 10 .1) (Garcia et al., 2002) . Acute diarrhea following shipment was associated with EPEC O145:H2 infection in laboratory rabbits (Swennes et al., 2012) . Laboratory rabbits can be reservoir hosts of pathogenic E. coli without exhibiting clinical signs (García and Fox, 2003; Swennes et al., 2013) . Patent or occult blood may be detected in the feces of infected rabbits (Camguilhem and Milon, 1989; Garcia et al., 2002) .

Epizootiology EPEC and EHEC can be enzootic in rabbit colonies and these bacteria are transmitted by the fecal-oral route (García and Fox, 2003; Swennes et al., 2013; Swennes et al., 2012) . EPEC and EHEC coinfections are possible (García and Fox, 2003; Garcia et al., 2002) . EHEC are a subset of STEC that carry stx gene(s) that encode Stx(s) and also carry the eae gene that encodes intimin (Melton-Celsa et al., 2012) . Rabbits can harbor STEC strains and are recognized as their vectors and reservoir hosts (Bailey et al., 2002; Blanco et al., 1996; García and Fox, 2003; Kim et al., 1997; Leclercq and Mahillon, 2003; Pohl et al., 1993; Pritchard et al., 2001; Scaife et al., 2006) .

Pathology Grossly, paintbrush hemorrhages of the cecal serosa may be observed after experimental infection with EPEC (Camguilhem and Milon, 1989) . Also, experimentally, the serosal surface of the cecum and/or proximal colon can develop petechial or echymotic hemorrhages and may become edematous and thickened (García et al., 2006) . Histologically and ultrastructurally, attaching and effacing lesions with pedestal formation can be observed with EPEC or EHEC infections (Kaper et al., 2004; Peeters et al., 1988) . Enterocolitis, nephropathy, and thrombotic microangiopathy can be observed in EHEC-infected rabbits (García et al., 2006) .

Diagnosis Feces or intestinal contents can be enriched in broth and then cultured using blood agar, MacConkey agar, or EHEC-selective media such as Sorbitol MacConkey agar or Raibow® agar (García and Fox, 2003; Tarr, 2009; Tarr et al., 2005) . After isolation of E. coli in pure culture, samples can be biotyped using commercial methods such as the API® 20E strips (bio-Mérieux). Serotyping and molecular characterization of isolates can be performed by the E. coli Reference Center (http://ecoli.cas.psu.edu/) at The Pennsylvania State University. PCR assays can be utilized to detect virulence factors characteristic of EPEC, EHEC, or other pathogenic E. coli as well as for high-resolution genotyping for epidemiological studies (Blanco et al., 1996; García and Fox, 2003) . Molecular characterization of STEC strains can be performed by the STEC Center (http://www. shigatox.net/new/) at Michigan State University.

Differential Diagnoses The differential diagnoses should include other causes of diarrhea in rabbits including the clostridial diseases and intestinal coccidiosis.

Treatment, Prevention, and Control For prevention, avoid introduction of rabbits of unknown pathogenic E. coli status into a colony. Rabbits should be screened by culture and E. coli isolates characterized for virulence factors by PCR. Also, since it is known that EHEC can contaminate plants and vegetables, laboratory personnel should be aware that rabbit feeds such as hay, alfalfa, and other greens have the potential to introduce enteric pathogens such as EHEC into laboratory rabbits (Berger et al., 2010; García and Fox, 2003) . EHEC O157 can survive for 60 days in grass hay feed (Davis et al., 2005) .

Cesarean section rederivation and antibiotic treatment have been suggested for eradication of pathogenic E. coli in rabbits (Swennes et al., 2012) . A 'One Health' approach should be incorporated to control EHEC infections because outbreaks such as with EHEC O157 in humans was linked to consumption of spinach contaminated by feral swine and was additionally isolated from domestic cattle, surface water, sediment, and soil (Garcia et al., 2010 ) -a good example of integrating human, animal, and environmental health (Monath et al., 2010) .

Antibiotic treatment should be based on culture and sensitivity. Importantly, in humans infected with EHEC, treatment with antibiotics is controversial due to the possibility of induction of Stx-encoding bacteriophages and worsening of the clinical condition due to Hemolytic Uremic Syndrome (Tarr et al., 2005) ; therefore, antibiotic treatment of rabbits infected with EHEC may not be recommended. Clinically affected rabbits can be treated with fluids as this intervention is nephroprotective in humans (Hickey et al., 2011) . In addition, rabbit EPEC strains may carry extended-spectrum beta-lactamases making them resistant to antibiotics (Poeta et al., 2010) . Parenteral enrofloxacin administered prior to shipment decreased morbidity and mortality associated with endemic EPEC (Swennes et al., 2012) .

Research Complications EPEC infection can cause high morbidity and mortality in laboratory rabbit colonies and can affect studies involving intestinal physiology in rabbits. EPEC and EHEC present a zoonotic risk (Garcia et al., 2010; Poeta et al., 2010; Swennes et al., 2013) .

Etiology Treponema paraluiscuniculi is a noncultivable species that infects rabbits and causes venereal spirochetosis or treponematosis (also known as rabbit syphilis, vent disease, or cuniculosis) (Smajs et al., 2011) . Although its genome structure is closely related to other pathogenic Treponema species including T. pallidum subsp. pallidum, the etiological agent of human syphilis, T. paraluiscuniculi does not infect humans (Smajs et al., 2011) . Genome sequencing revealed that T. paraluiscuniculi evolved from a T. pallidum-like ancestor and adapted to rabbits during loss of infectivity to humans (Smajs et al., 2011) . T. paraluiscuniculi can also infect hares, and causes seroconversion, but no clinical signs. In contrast, the related organism, T. paraluisleporis, can infect and induce disease in rabbits and hares. The close phylogenetic association between T. paraluiscuniculi and T. paraluisleporis suggests that these organisms could be given a subspecies or ecovar status rather than species status (Lumeij et al., 2013) .

Clinical Signs In naturally infected rabbits lesions commonly occur in the vulva or prepuce (Cunliffe-Beamer and Fox, 1981a) . Other parts of the body that may be affected, in descending order, include the anal region, nose, eyelid, and lip (Cunliffe-Beamer and Fox, 1981a) . Naturally infected rabbits develop lesions of the ear, face, prepuce, and anus (Small and Newman, 1972) . In a study involving intratesticular inoculation of T. paraluiscuniculi, single lesions were found in the prepuce or scrotum and multiple lesions were found in the nose, mouth, ear, prepuce, foot, and scrotum (Small and Newman, 1972) . All lesions had abundant treponemes by dark-field examination (Small and Newman, 1972) .

Epizootiology Susceptibility to, and expression of venereal spirochetosis, may vary with the strain of rabbit (Cunliffe-Beamer and Fox, 1981b) . The prevalence of T. paraluiscuniculi infection increased with parity in adult females and most adult males seroconverted within 6 months of entering the breeding program. These findings suggested that T. paraluiscuniculi spreads by horizontal transmission in adult rabbits (DiGiacomo et al., 1983) . In an enzootically infected conventional rabbit colony, the frequency of venereal spirochetosis was lower in rabbits less than 6 months of age than in adult rabbits (Cunliffe-Beamer and Fox, 1981b) . Experiments involving cross fostering of newborns indicated that infection occurred at birth (vertical transmission) and during the suckling period (Cunliffe-Beamer and Fox, 1981b) . In addition, horizontal transmission by coitus and skin contact occurs (Small and Newman, 1972) . Experimental topical or intradermal-subcutaneous genital inoculation of adult rabbits confirmed these routes of transmission (Cunliffe-Beamer and Fox, 1981b) .

The T. pallidum repeat (tpr) genes in T. pallidum subsp. pallidum are thought to code for potential virulence factors. TprK was the only Tpr homolog found in T. paraluiscuniculi that induced antibody and T cell responses after experimental inoculation of rabbits indicating that TprK may be an important virulence factor in venereal spirochetosis (Giacani et al., 2004) . Virulence factors and pathogenesis have been recently reviewed (Smajs et al., 2012) .

Pathology The lesions include erythemathous macules or papules to erosions, ulcers, and crusts (Cunliffe-Beamer and Fox, 1981a) .

Diagnosis Serologic tests that have been used include the nontreponemal antigen tests (Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin), microhemagglutination, and fluorescent treponemal antibody absorption tests (DiGiacomo et al., 1983) . Although the nontreponemal antigen tests were not completely satisfactory, the VDRL test was more sensitive and the plasma reagin test was more specific in detecting T. paraluiscuniculi infection (DiGiacomo et al., 1983) . The sensitivity and specificity of the microhemagglutination test compared favorably with the fluorescent treponemal antibody absorption test and was recommended as the optimal assay to make a diagnosis (DiGiacomo et al., 1983) . Detection of T. paraluiscuniculi in lesions can be achieved by dark-field microscopic examination of scrapings from lesions and by histological evaluation of silver-stained testicular sections (Cunliffe-Beamer and Fox, 1981a; Faine, 1965) . PCR has been used for molecular characterization of treponemes including T. paraluiscuniculi (Cejkova et al., 2013) .

Differential Diagnoses The skin lesions may be confused with abrasions (trauma), mycotic infections, and lesions of ectoparasites (acariasis) (Small and Newman, 1972) .

Treatment, Prevention, and Control There are no vaccines available at this time to prevent treponematosis in rabbits; however, rabbits have been used as experimental models to test vaccines against T. pallidum in humans (Ho and Lukehart, 2011) . Hysterectomy derivation can eliminate venereal spirochetosis (Cunliffe-Beamer and Fox, 1981b) . A study investigating two different doses (42,000 or 84,000 IU/kg body weight/ week) of benzathine penicillin G-procaine penicillin G to treat rabbits at 7-day intervals found that both dosages were effective. Lesions healed within 2 weeks of the first treatment and the plasma reagin titers declined markedly or disappeared by the sixth week after the first treatment (Cunliffe-Beamer and Fox, 1981c) .

Research Complications T. paraluiscuniculi can affect studies of T. pallidum in rabbits (Small and Newman, 1972) . Partial immunological cross-protection has been observed between T. paraluiscuniculi and T. pallidum (Smajs et al., 2011; Turner and Hollander, 1957) .

Etiology Lawsonia intracellularis is a Gram-negative, curved to spiral-shaped, obligate intracellular bacterium that causes proliferative enteropathy in rabbits and other species of animals (Sait et al., 2013; Schauer et al., 1998) .

Clinical Signs An intraepithelial 'vibrio' was associated with acute typhlitis in rabbits 1-4 weeks after weaning (Moon et al., 1974) . Diarrhea was reported in Japanese White rabbits with presumptive L. intracellularis infection and histiocytic enteritis (Umemura et al., 1982) . In another report, sucklings and weanlings were affected and the feces of most of the rabbits were characterized as semifluid and mucinous or pasty, and three rabbits had watery diarrhea (Schoeb and Fox, 1990) . These affected rabbits were afebrile and lethargic, refused food and water, and most died within a few days after the onset of diarrhea (Schoeb and Fox, 1990) . Diarrhea, depression, and dehydration that resolved over the course of 1-2 weeks were reported in 5-to 8-week-old New Zealand White (NZW) rabbits (Hotchkiss et al., 1996) . Diarrhea and weight loss were reported in a 3-month-old rabbit (Horiuchi et al., 2008 ). An outbreak of diarrhea with high (70%) mortality was reported in 2-to 4-month-old NZW rabbits with proliferative enterocolitis associated with L. intracellularis and EPEC (Schauer et al., 1998) .

Epizootiology Proliferative enteropathy generally occurs as isolated cases or occasional minor outbreaks in species other than the pig, blue fox, and hamster (Lawson and Gebhart, 2000) . Infected rabbits can serve as reservoir hosts for L. intracellularis infection in other species including foals (Pusterla et al., 2012a (Pusterla et al., , 2013 . However, L. intracellularis appears to adapt to the specific animal species it infects (Vannucci et al., 2012) .

The pathogenesis of L. intracellularis infection has been reviewed (Lawson and Gebhart, 2000; Smith and Lawson, 2001) . Studies using interferon (IFN)-gamma receptor knockout mice determined that interferon IFNgamma plays a significant role in limiting intracellular infection and increased cellular proliferation associated with L. intracellularis infection (Smith et al., 2000) . Lawsonia surface antigen (LsaA) plays a role during L. intracellularis attachment to and entry into intestinal epithelial cells (McCluskey et al., 2002) . BALB/cA mice are susceptible to rabbit L. intracellularis isolates but not to pig L. intracellularis isolates suggesting that there are biological differences between the proliferative enteropathy isolates from rabbits and pigs (Murakata et al., 2008) .

Pathology Distention and diffuse mucosal thickening of the jejunum and proximal ileum with enlarged cranial mesenteric lymph nodes was observed in 5-to 6-month-old rabbits (Umemura et al., 1982) . Thickening of the mucosa was associated with distention of the lamina propria with macrophages and the enlargement of the lymph nodes was also associated with infiltration of macrophages (Umemura et al., 1982) . Minute bacilli were observed in the apical cytoplasm of mucosal epithelial cells using toluidine blue (Umemura et al., 1982) . Thickening of the cecum and proximal colon has also been reported (Hotchkiss et al., 1996) . In another study, no gross lesions were found in the small intestine, but two suckling rabbits had reddened ceca with congested vessels (Schoeb and Fox, 1990) . In this study two types of microscopic lesions were characterized: (1) erosive and suppurative cecitis and colitis, and (2) proliferative lesions in the cecum, sacculated colon, ileum, and distal jejunum, or a combination of these (Schoeb and Fox, 1990) . Some animals had both erosive and proliferative lesions. Narrow curved or spiral bacteria were detected in rabbits with erosive and proliferative lesions using Warthin-Starry stain and these bacteria were more abundant in cases with severe lesions (Schoeb and Fox, 1990) . Proliferative intestinal lesions contained curved to spiral argyrophilic intracellular bacteria in the apical cytoplasm of crypt enterocytes (Hotchkiss et al., 1996) .

Diagnosis The 16S ribosomal DNA sequences from L. intracellularis isolates from different species of animals are highly similar (Cooper et al., 1997a) . However, antigenic differences have been found between pig and rabbit isolates . The complete genome sequence of a porcine strain has been recently reported (Sait et al., 2013) . L. intracellularis can be detected in feces from healthy and diarrheic rabbits (Lim et al., 2012) .

PCR assays to detect L. intracellularis DNA in feces have been evaluated (Pedersen et al., 2010) . These assays can be used for ante mortem diagnosis of proliferative enteropathy in pigs (Pedersen et al., 2010) . PCR primers used to diagnose Lawsonia in other animals species have been used in rabbit cases (Cooper et al., 1997b; Duhamel et al., 1998; Fox et al., 1994; Horiuchi et al., 2008; Hotchkiss et al., 1996; Jones et al., 1993) . Other diagnostic methods include enzyme-linked immunosorbent assay (ELISA) using synthetic peptides of LsaA and immunomagnetic separation using anti-LsaA antibody to capture L. intracellularis in fecal samples followed by detection with ATP bioluminescence (Watarai et al., 2004 (Watarai et al., , 2005 . In tissue sections, L. intracellularis can be detected using silver stains such as Warthin-Starry stain (Duhamel et al., 1998; Horiuchi et al., 2008; Hotchkiss et al., 1996; Schauer et al., 1998; Schoeb and Fox, 1990) . Indirect immunofluorescence has also been used in deparaffinized intestinal sections from infected rabbits (Schoeb and Fox, 1990) . Immunohistochemistry using antiserum against synthetic peptides of LsaA has also been used to detect L. intracellularis in the ileum of a naturally infected rabbit (Watarai et al., 2004) . Electron microscopy reveals organisms that are ~0.23-0.32 μm wide and ≤ 1.7 μm long in the apical cytoplasm of villous and crypt epithelial cells (Duhamel et al., 1998) . L. intracellularis can be cultured from homogenized intestinal tissue in cell lines including IEC-18 (rat small intestinal cells) and McCoy cells (mouse fibroblasts) (Lawson and Gebhart, 2000; Watarai et al., 2008) . A quantitative PCR (qPCR) assay that is able to assess the growth of L. intracellularis in cultured cells has also been used to detect the organisms in pig fecal samples and could be used in other animal species (Drozd et al., 2010) .

Differential Diagnoses Clinically, the differential diagnosis should include other causes of diarrhea in rabbits. Mycobacterium avium subsp. paratuberculosis can infect rabbits and induce thickening of the intestinal mucosa (Beard et al., 2001; Greig et al., 1997) . Therefore, rabbit intestinal sections should be examined for acidfast organisms using stains such as Ziehl-Neelsen stain (Duhamel et al., 1998; Horiuchi et al., 2008; Schoeb and Fox, 1990; Umemura et al., 1982) . Furthermore, other intestinal organisms may colonize the intestine during L. intracellularis infection in rabbits (Duhamel et al., 1998; Hotchkiss et al., 1996; Lim et al., 2012; Schauer et al., 1998) . Other bacterial diseases have been sporadically reported in rabbits. These are summarized in Table 10 .6.

Treatment, Prevention, and Control Vaccination strategies have been tested and developed for pigs and horses, but not for rabbits (Nogueira et al., 2013; Pusterla et al., 2012b; Weibel et al., 2012) . Testing rabbits by PCR prior to introduction to a laboratory colony may be necessary for exclusion of this organism. Oral neomycin (50 mg/rabbit) was used to treat surviving rabbits during an outbreak of presumptive L. intracellularis and the diarrhea subsided (Umemura et al., 1982) . Because L. intracellularis infects the intestine and IFN-gamma appears to be involved in pathogenesis, research involving rabbit gastrointestinal pathology and immune responses may be confounded by infection with this organism.

Research Complications The mortality associated with L. intracellularis infection would be disruptive to ongoing studies.

Etiology Myxomatosis is caused by myxoma virus, a member of the family Poxviridae, genus Leporipoxvirus (Kerr and Donnelly, 2013; Spiesschaert et al., 2011) .

Clinical Signs The severity of disease varies with the strain of virus and the host species and breed. Rabbits of the genus Oryctolagus are particularly susceptible and often develop a fatal disease characterized by mucinous skin lesions and tumors. Affected animals also exhibit edema around the mouth, nose, anus, and genitals as well as progressive conjunctivitis with serous and mucopurulent secretions from the eyes and nose (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013; Spiesschaert et al., 2011) . Bacterial pneumonia commonly develops and animals die 10-14 days after infection. The virus is spread by arthropod vectors and direct contact.

Epizootiology Myxomatosis has a worldwide distribution. Various species of Sylvilagus and Lepus are naturally susceptible (Brabb and Di Giacomo, 2012) . The myxoma virus genome encodes for a number of immunomodulatory proteins which greatly affect the host immune response by inhibiting apoptosis, interfering with leukocyte chemotaxis, and suppressing leukocyte activation, thereby fostering viral replication and spread (Spiesschaert et al., 2011) .

Pathology Histopathology shows these 'myxomas' to be composed of undifferentiated stellate mesenchymal cells embedded in a matrix of mucinous material and interspersed with capillaries and inflammatory cells (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) .

Diagnosis Diagnosis can be made by PCR or ELISA. Definitive diagnosis depends on culture of the virus from infected tissues.

Differential Diagnoses Rabbits of the genus Sylvilagus develop fibroma-like lesions that may be indistinguishable from those caused by rabbit fibroma virus. The two diseases have been distinguished by inoculation of fibroma material into Oryctolagus rabbits. They develop fatal disease if the myxoma virus is the etiologic agent, or fibromas if rabbit fibroma virus is responsible.

Treatment, Prevention, and Control Since the disease is spread by fleas and mosquitoes as well as by direct contact, control measures should include prevention of contact with arthropods and quarantine of infected rabbits. Vaccines have been used in Europe with some success. Most recently, a live recombinant vaccine for both myxomatosis and rabbit hemorrhagic disease has been released in the United Kingdom (Spibey et al., 2012) .

Research Complications None have been reported.

Rabbit (Shope) fibroma virus is a Leporipoxvirus that is antigenically related to myxoma virus. Fibromatosis is endemic in wild rabbits; however, an outbreak in commercial rabbits caused extensive mortality (Joiner et al., 1971) . Usually, less virulent strains cause skin tumors in domestic rabbits (Raflo et al., 1973) . The disease is probably spread by arthropods (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) . Fibromas are flat, subcutaneous, easily movable tumors, and most often found on the legs and face. Tumors may persist for some time but eventually regress. Metastasis does not occur.

Rabbit pox is a rare disease induced by an Orthopoxvirus taxonomically similar to vaccina virus that has caused outbreaks of fatal disease in laboratory rabbits in the United States and Holland (Brabb and Di Giacomo, 2012) . Rabbits with the disease may or may not present with 'pox' lesions in the skin. The animals have a fever and nasal discharge 2 or 3 days after infection. Most rabbits have eye lesions including blepharitis, conjunctivitis, and keratitis with subsequent corneal ulceration. Skin lesions, when present, are widespread. They begin as a macular rash and progress to papules up to 1 cm in diameter by 5 days postinfection. The lymph nodes are enlarged, the face is often edematous, and there may be lesions in the oral and nasal cavity. At gross necropsy, nodules can be found in the liver, gall bladder, spleen, lung, and reproductive organs. Necrosis is widespread. Characteristic cytoplasmic inclusions seen in many poxvirus infections are rare in this disease. Mortality is high in affected animals. The virus is apparently spread by aerosols and is difficult to control. Rabbit pox is used as a model of smallpox in humans in response to the potential use of smallpox as a bioterrorism agent. It is an effective model for the evaluation of potential therapies against smallpox (Nalca and Nichols, 2011; Rice et al., 2011) .

Four herpesviruses (leporid herpesviruses 1, 2, 3, and 4) have been isolated from rabbits and hares (Davison, 2010) . Leporid herpesvirus 1 (LHV-1) was isolated from cottontail rabbits and is also known as cottontail rabbit herpesvirus. It is not pathogenic for domestic rabbits. LHV-2 (Herpesvirus cuniculi) was isolated from domestic rabbits (O. cuniculus) and causes subclinical infections. LHV-3 (Herpesvirus sylvilagus) was isolated from cottontail rabbits. Cottontail rabbits infected with the virus develop a lymphoproliferative disease with lymphoid infiltration of many organs (Hesselton et al., 1988) . LHV-3 does not infect domestic rabbits. LHV-1-3 are tentatively classified in the genus Radinovirus, subfamily Gammaherpesvirinae. LHV-4 was isolated from domestic rabbits and caused severe disease in preweanlings (Jin et al., 2008a, b) . Clinical signs included weakness, anorexia, conjunctivitis, keratitis, and periocular swelling. Some animals also developed skin ulcers. LHV-4 is genus Simplexvirus, subfamily Alphaherpesvirinae.

The cottontail rabbit is the natural host of the cottontail (Shope) papillomavirus, a Kappapapillomavirus, 

LABORATORY ANIMAL MEDICINE which causes horny warts primarily on the neck, shoulders, and abdomen. The disease has a wide geographic distribution with the highest incidence occurring in rabbits in the midwest (Brabb and Di Giacomo, 2012) . As many as 25% of infected Sylvilagus rabbits develop squamous cell carcinomas. Natural outbreaks in domestic rabbits have been reported (Hagen, 1966) . In these natural outbreaks, papillomas were more common on the eyelids and ears. The virus is transmitted by arthropod vectors. This virus is used extensively as a model for the study of oncogenic virus biology and as a model for the treatment and prevention of papillomavirus infections in humans (Christensen, 2005; Salmon et al., 1997; Sundarum et al., 1998) . Oral papillomatosis in domestic rabbits is caused by a Kappapapillomavirus that is related to but distinct from the cottontail rabbit papilloma virus. Naturally occurring lesions have been seen in laboratory rabbits and appear as small, white, discrete growths on the ventral surface of the tongue (Kerr and Donnelly, 2013) . Lesions may ulcerate. Microscopic examination shows them to be typical papillomas. Most lesions eventually regress spontaneously (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) .

Etiology Rabbit rotavirus is a member of the family Reoviridae. All isolates of rabbit rotavirus have been classified as group A and have been serotype 3 (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) .

Clinical Signs The severity of disease in naturally occurring outbreaks has been variable. In severe outbreaks, affected animals exhibit anorexia, dehydration, and watery to mucoid diarrhea and mortality can be quite high. In other reported outbreaks, mild, transient diarrhea has been reported (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) .

Similarly, attempts to experimentally produce clinical disease have had variable results. Mild diarrhea is usually seen, but in some studies there has been significant mortality. It is probable that other factors, such as maternal antibodies, diet, and the presence of pathogenic bacteria, affect the severity of clinical disease in outbreaks. For example, in combined experimental infections with both rotavirus and E. coli, the inoculation of both organisms led to more serious clinical signs than when given alone, indicating that rotavirus may have been a more significant determinant in the manifestation of this disease (Thouless et al., 1996) . These investigators also showed that older rabbits were naturally more resistant to the combined infection with rotavirus and E. coli.

Epizootiology Rotavirus infections of domestic rabbits are common (Brabb and Di Giacomo, 2012) . Many colonies of rabbits are serologically positive, and rotavirus can be isolated readily from rabbit feces. In endemically infected colonies, maternal antibodies to rotaviruses are passed transplacentally and decline at around the time of weaning (Brabb and Di Giacomo, 2012) . Rabbits of weaning age are most susceptible.

Very young rabbits appear to be protected from rotavirus infection by passive immunity, when present, but are quite susceptible when there is none (Schoeb et al., 1986) . This is also the time when they are most likely to be subjected to diet changes that may contribute to a change in microbial flora.

Pathology In affected animals, there is villous atrophy and loss of epithelial cells in the small intestines. A lymphocytic infiltrate is present.

Diagnosis Immunoassays (ELISA and multiplex fluorescent immunoassay) are commercially available for rabbit rotavirus. A commercial immunochromatography kits for detecting human rotavirus infection was used successfully to diagnose rabbit rotavirus infection (Fushuku and Fukuda, 2006) . Differential Diagnoses C. piliforme, C. spiroforme, C. difficile, E. coli, Lawsonia intracellularis, coronavirus, coccidiosis, and intestinal parasites should be considered.

Research Complications Colony mortality would be disruptive to ongoing studies.

Pleural effusion disease/infectious cardiomyopathy was diagnosed in rabbits inoculated with T. palliduminfected stocks of testicular tissue. Because these treponemes could not be grown in vitro, the organism was propagated by passage in rabbits. The stocks were contaminated with a coronavirus, although it is not known whether this virus originated from rabbits or was a virus of human origin that had adapted to rabbits. With continued passage, the virus became more virulent, and significant mortality ensued. Evidence indicated that it was not transmitted by direct contact. Rabbits died due to congestive heart failure, and microscopic examination showed there was widespread necrosis of the heart muscle. It has been suggested that infection with this virus might be a model for the study of virus-induced cardiomyopathy (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) .

Rabbit enteric coronavirus has been isolated from tissue cultures from rabbits (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013; Lapierre et al., 1980) and has been associated with one naturally occurring outbreak of diarrhea in a barrier-maintained breeding colony (Eaton, 1984) . These rabbits developed severe diarrhea, and most died within 48 h of onset of clinical signs. Attempts to reproduce the disease led to watery diarrhea, which lasted a short time; however, none of the rabbits died. It is quite probable that other microorganisms or LABORATORY ANIMAL MEDICINE unknown environmental factors contributed to the severity of this outbreak.

Etiology Rabbit hemorrhagic disease virus is a calicivirus of the genus Lagovirus and is the causative agent of rabbit hemorrhagic disease (RHD) (Abrantes et al., 2012; Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) .

Clinical Signs Three clinical syndromes are seen (Abrantes et al., 2012) . The peracute form is characterized by sudden death without clinical signs. Acutely affected animals demonstrate anorexia and depression. In addition, neurologic signs, respiratory signs, ocular hemorrhage, and epistaxis may be seen. Morbidity and mortality are extremely high. Lymphopenia and abnormalities in coagulation parameters are also seen. In the subacute form, similar signs may occur but are considerably milder and most of these rabbits survive (Abrantes et al., 2012; Kerr and Donnelly, 2013) .

Epizootiology Rabbit hemorrhagic disease was first reported in China in 1984 and is currently endemic in Europe, Asia, Africa, Australia, and New Zealand. In addition, isolated outbreaks have been reported in numerous countries.

The virus is transmitted by the fecal-oral route. The role of fomites and arthropod vectors is also suspected (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) . The incubation period may be as short as 1 or 2 days, and sudden death with no previous signs is common.

Pathology Periportal hepatic necrosis is the only consistent microscopic lesion, and the animals die due to disseminated intravascular coagulopathy and thrombosis (Abrantes et al., 2012; Kerr and Donnelly, 2013) .

Diagnosis The virus has not been successfully grown in vitro; however, diagnosis can be confirmed with negative-contrast electron microscopy of liver tissue. Specific antibodies can be detected by ELISA or by hemagglutination inhibition.

Differential Diagnoses A related calicivirus, European brown hare virus, has caused disease in hares in several countries in Europe (Brabb and Di Giacomo, 2012) . Animals present with necrotic hepatitis, hemorrhages in the trachea and lungs, and pulmonary edema. A monoclonal antibody ELISA is available for serodiagnosis, and control measures are similar to those for RHD.

The agent resists drying, can be carried on fomites, and may be transmitted via respiratory and intestinal secretions (Mitro and Krauss, 1993) . Any rabbit colonies with this disease should be quarantined and depopulated, and the environment thoroughly cleansed and disinfected.

Research Complications Colony mortality would be disruptive to ongoing studies.

Other Viral Infections Several other viruses have been isolated from rabbit tissues, but have not been shown to produce disease. These include paramyxoviruses and bunyaviruses. Serologic titers to togaviruses and flaviviruses have also been demonstrated in rabbits (Brabb and Di Giacomo, 2012; Kerr and Donnelly, 2013) .

Etiology Hepatic coccidiosis is caused by the parasite Eimeria stiedae, which has also been referred to as Monocystis stiedae, Coccidium oviforme, and C. cuniculi (Hofing and Kraus, 1994) .

Clinical Signs The clinical disease has a wide range of manifestations. Mild infections often result in no apparent disease. Most clinical signs are the result of interruption of normal hepatic function and blockage of the bile ducts. These signs are more common in juvenile rabbits and can include hepatomegaly, icterus, and anorexia (Schoeb et al., 2007) . Diarrhea can occur at the terminal stages of the disease (Hofing and Kraus, 1994) . Decreased growth rates and weight loss are common. Joyner et al. (1987) demonstrated that infected rabbits begin to lose weight within 15 days.

Enlargement of the liver (hepatomegaly) is common. The liver normally is approximately 3.7% of the body weight, but rabbits with severe hepatic coccidiosis may have livers that contribute to greater than 20% of the body weight (Lund, 1954b) .

The age of the host strongly affects parasite development and oocyst production. Four-month-old, coccidia-free rabbits experimentally infected with E. stiedae produced fewer oocysts than similarly infected 2-monthold rabbits (Gomez-Bautista et al., 1987) .

Epizootiology E. stiedae is found worldwide, although rabbits bred for use in research are commonly free of the parasite. Transmission occurs by the fecaloral route, as for other coccidia. The organism has also been experimentally transmitted by intravenous, intraperitoneal, and intramuscular administration of oocysts (Pellérdy, 1969) . Smetana (1933) demonstrated that infection of the entire liver occurred following ligation of the right bile duct and inoculation of E. stiedae oocysts. The study also showed that infection occurred earliest within the small intrahepatic ducts, leading to the theory that infection occurred via blood or lymph. The precise life cycle is still undetermined, although a number of studies have examined it (Horton, 1967; Owen, 1970; Rose, 1959) . Sporozoites have been demonstrated in the lymph nodes following experimental inoculation (Horton, 1967; Rose, 1959) .

Pathology Necropsy often shows the liver to be enlarged and discolored, with multifocal yellowish LABORATORY ANIMAL MEDICINE white lesions of varying size (Fig. 10.2) . Exudate in the biliary tree is common, along with dilatation of bile ducts. Microscopically, papillomatous hyperplasia of the ducts along with multiple life-cycle stages of the organism can be observed in the biliary epithelium ( Fig. 10.3) .

Diagnosis Infected rabbits may have decreased fibrinogen when compared to uninfected rabbits (Cam et al., 2006) . Serum bilirubin levels can rise to 305 mg/ dl, increasing as soon as day 6 of infection and increasing through days 20-24 before moderating (Rose, 1959) . Leukocytosis and anemia can be observed and acute phase proteins are notably increased by 7 days post infection (Freitas et al., 2011) . Diagnosis can be made by examination of fecal material, by either flotation or concentration methods. Oocysts can also be detected within the gallbladder exudate (Hofing and Kraus, 1994) . Alternatively, oocysts can sometimes be observed by microscopic examination of impression smears of the cut surface of the liver. Ultrasonography may be a useful tool for diagnosis, with dilated vessels and bile ducts and increased echogenicity of the liver parenchyma (Cam et al., 2008) .

Differential Diagnoses The hyperplastic biliary ducts can be mistaken grossly for neoplasia. Other types of parasitic hepatitis should be considered as differential diagnoses. Less frequently, hepatitis secondary to bacterial infections can occur.

Treatment, Prevention, and Control Control of the infection until development of natural immunity is one strategy to minimize the severity of disease. Davies et al. (1963) demonstrated that immunity occurs following a light infection with E. stiedae. In the rabbit, immunity to Eimeria may be lifelong (Niilo, 1967; Pellérdy, 1965) . Prevention of hepatic coccidiosis with sulfaquinozaline in the feed (250 ppm) was shown to prevent infection when experimental challenged with 100,000 sporulated oocysts (Joyner et al., 1987) . Sulfonamides have been shown effective against Eimeria spp. (Hagen, 1958; Horton-Smith, 1947; Jankiewicz, 1945; Lund, 1954a; Tsunoda et al., 1968) . Treatment with toltrazuril (50 ppm in drinking water for one day) has been shown to effectively treat infected animals (Cam et al., 2008) . Thorough sanitation of potentially contaminated surfaces is critical to control of coccidiosis.

Research Complications Potential research complications arising from hepatic coccidiosis are considerable. The resulting liver damage and decreased weight gains can complicate both the supply of rabbits for research as well as adversely affect research protocols.

Etiology There are at least 14 different pathogenic species of intestinal coccidia in rabbits, including Eimeria coecicola, E. elongate, E exigua, E. intestinalis, E. flavescens, E. irresidua, E. magna, E. matsubayashii, E. media, E. nagnurensis, E. neoleporis, E. piriformis, E. vejdovskyi, and E. perforans (Pakandl, 2009 ). All of these coccidia are presented here as a group rather than as individual species of intestinal coccidia.

Clinical Signs Although intestinal coccidiosis may be subclinical, clinical signs can range from mild to severe and can result in death of the animal. Postweanling rabbits are the most likely to experience mortality related to intestinal coccidiosis. Suckling rabbits (<20 days old) are generally considered to be resistant to infection (Pakandl and Hlaskova, 2007) . Clinical signs also depend on the species of coccidia that are present. Severe diarrhea, weight loss, or mild reduction in growth rate are all LABORATORY ANIMAL MEDICINE possibilities. Fecal occult blood may be detected with E. perforans infection (Li and Ooi, 2009) . Death is usually associated with severe dehydration subsequent to diarrhea (Frenkel, 1971) .

Epizootiology Intestinal coccidiosis is a common rabbit disease worldwide (Varga, 1982) . Transmission is by the fecal-oral route through ingestion of sporocysts. Unsporulated oocysts are passed in the feces and are not infective. Such oocysts will, however, sporulate to an infective stage within 3 days after shedding; thus, it is important that sanitation be frequent enough to remove infective stages from the environment. The oocyst burden of feces can be enormous. Gallazzi (Gallazzi, 1977) demonstrated that a subclinical carrier of intestinal coccidia had 408,000 oocysts/gram of feces and that a rabbit with diarrhea could shed in excess of 700,000 oocysts/gram of feces. Environmental contamination with oocysts can be a problem when large numbers of oocysts are being excreted.

The life cycles of Eimeria spp. are similar to those of other coccidia. Schizogony, gametogony, and sporogony are the three phases of this life cycle. Other sources can be consulted for greater detail on the life cycle of these protozoans (Davies et al., 1963; Pakandl, 2009; Pakandl and Jelinkova, 2006; Pellérdy, 1965; Rutherford, 1943) .

Pathology Lesions are apparent in the small and large intestines. Necrotic areas of the intestinal wall appear as white foci (Pakes, 1974; Pakes and Gerrity, 1994) . The location and extent of the lesions depend on the species of coccidia.

Diagnosis Diagnosis of intestinal coccidiosis can be made through identification of the oocysts in the feces (Pakes and Gerrity, 1994) . A PCR has been developed (Oliveira et al., 2011) that differentiates between 11 of the different Eimeria species that infect the domestic rabbit. This test has excellent sensitivity, with the ability to detect 0.8-1.7 sporulated oocysts per sample. Smaller scale PCR for detection and differentiation between the more pathogenic species (E. intestinalis, E. flavicenens, and E. stiedae) has also been developed (Yan et al., 2013) .

Differential Diagnoses Other causes of diarrhea in rabbits should be considered including Tyzzer's disease, the Clostridial diseases, colibacillosis, L. intracellularis, enteric coronovairus and rotavirus, protozoons, or intestinal parasites.

Treatment, Prevention, and Control Because intestinal coccidiosis is most common in postweanling rabbits, prevention of the disease should focus on the preweaning period. An oral vaccination has been developed and consists of a nonpathogenic strain of E. magna. This vaccine is sprayed into the nest box when rabbits are 25 days of age. The preweanling rabbits develop immunity subsequent to infection with the nonpathogenic strain and are then resistant to wild-type strains of E. magna at 35 days of age (Drouet-Viard et al., 1997) .

Other oral vaccines developed from various Eimeria strains are also in development (Akpo et al., 2012) .

Prevention and control of infection can be accomplished by providing 0.02% sulfamerazine or 0.05% sulfaquinoxaline in the drinking water (Kraus et al., 1984) . A combination of sulfaquinoxaline, strict sanitation, and elimination of infected animals has been shown to eliminate intestinal coccidiosis from a rabbit breeding colony (Pakes and Gerrity, 1994) . As for hepatic coccidiosis, sulfaquinoxaline provided in the feed (250 ppm) is an effective treatment.

Research Complications Intestinal coccidiosis can impact studies of the gastrointestinal tract, or have an impact on survival of postweanling rabbits.

Etiology The protozoan organism Cryptosporidium cuniculus has been found in the intestinal tract of the rabbit (Hadfield and Chalmers, 2012; Inman and Takeuchi, 1979; Kaupke et al., 2014; Rehg et al., 1979; Robinson et al., 2010; Shiibashi et al., 2006; Zhang et al., 2012) .

Clinical Signs Clinical signs related to cryptosporidiosis seem to be quite variable in the rabbit. A large farm outbreak (Kaupke et al., 2014) had rabbits that presented with lethargy, anorexia and diarrhea. Animals showing clinical signs died within 5-10 days. The stress of weaning is thought to have exacerbated these signs. Another report describes small intestinal dilatation observed during surgery in a rabbit without other clinical signs (Inman and Takeuchi, 1979) .

Epizootiology Transmission is likely via ingestion of thick-walled sporulated oocysts. Experimentally infected juvenile rabbits began shedding oocysts in their feces 4-7 days post infection and continued to shed until 14 days post infection without clinical signs (Robinson et al., 2010) .

Pathology Histopathology of the small intestine of the reported rabbit was characterized by shortened, blunted villi and mild edema of the lamina propria. The lacteals of the ileum were also dilated, and an inflammatory response was observed (Inman and Takeuchi, 1979) .

Diagnosis C. cuniculus is emerging as a potential zoonotic pathogen with several reports in recent years (Chalmers et al., 2009 (Chalmers et al., , 2011 Zhang et al., 2012) . In response to this, real-time PCR assays are in development (Hadfield and Chalmers, 2012 ) that detect and differentiate C. cuniculus from C. parvum and C. hominis.

Differential Diagnoses C. cuniculus can only be differentiated from C. hominis and C. parvum via genetic analysis (Robinson et al., 2010) . Differential diagnoses would include infection with Clostridium piliforme, C. spiroforme, C. difficile, E. coli, Lawsonia intracellularis, coronavirus, rotavirus, protozoans, or intestinal parasites.

Treatment, Prevention, and Control Minimizing stress can possibly prevent or reduce clinical signs LABORATORY ANIMAL MEDICINE (Kaupke et al., 2014) . Antibiotics were ineffective in the large farm outbreak. Presumably, supportive care (fluids) would be indicated in animals showing clinical signs (Schoeb et al., 2007) . Prevention requires husbandry and sanitation practices that prevent exposure.

Research Complications This organism is emerging as a human pathogen, so appropriate precautions should be made to protect research personnel from rabbits positive for C. cuniculus.

Etiology The etiologic agent responsible for encephalitozoonosis is Encephalitozoon cuniculi. This agent is historically known by the name Nosema cuniculi (Pakes and Gerrity, 1994) and has been divided into three strains (I -rabbit strain, II -mouse strain, IIIdog strain) (Didier et al., 1995) . The disease was first described in 1922 as an infectious encephalomyelitis causing motor paralysis in young rabbits (Wright and Craighead, 1922) .

Clinical Signs Encephalitozoonosis typically has a delayed onset (weeks to months post infection) prior to the exhibition of clinical signs. Early infection affects the kidney, liver and lung, while alterations later in the infection are most severe in the kidneys and brain (Kunzel and Joachim, 2010) . The organism can be found in the tissues without an inflammatory response (Pakes and Gerrity, 1994) .

Although named for the motor paralysis in young rabbits, the disease is usually latent. If clinical signs are present, they can include convulsions, tremors, torticollis, paresis, and coma (Pattison et al., 1971) as well as signs of kidney failure. Intrauterine infection can result in phacoclastic uveitis leading to rupture of the lens capsule (Kunzel and Joachim, 2010) .

Epizootiology Transmission is likely horizontal via direct contact or environmental contamination (Kunzel and Joachim, 2010) , primarily from ingestion of infected urine (Schoeb et al., 2007; Wasson and Peper, 2000) . The pathogen can also be transmitted vertically, as evidenced by in utero PCR positivity reported by Baneux and Pognan (2003) .

Pathology The kidneys commonly have lesions at necropsy. Typically, there are multiple white, pinpoint areas or gray, indented areas on the renal cortical surface (Kraus et al., 1984) . Microscopically, these areas are characterized by granulomatous inflammation. Interstitial infiltration of lymphocytes and plasma cells and tubular degeneration may also be present (Flatt and Jackson, 1970) . Granulomatous encephalitis is a characteristic lesion (Fig. 10.4) (Pakes and Gerrity, 1994) . Lesions of the spinal cord can also occur (Koller, 1969) . The organisms are often not observed in histologic sections of the lesions. Organisms may be seen floating free in the tubules of the kidney (Pakes and Gerrity, 1994) .

Diagnosis Diagnosis of encephalitozoonosis can be made using several different methods. Histologic examination of tissues and observation of the organism is definitive. Brain and kidney samples yield the best detection rates for histopathological diagnosis (Leipig et al., 2013) . The Encephalitozoon organism does not stain well with hematoxylin and eosin, and is better demonstrated using Giemsa stain, Gram stain, or Goodpasture's carbol fuchsin stain (Pakes, 1974) . Many different serologic tests exist for the organism. Indirect fluorescence antibody technique and ELISA are both available and reliable (Kunzel and Joachim, 2010) .

Advances in diagnostic techniques have been made in human medicine due to the susceptibility of immunosuppressed patients to this particular infection. Several PCR tests for diagnosis and species differentiation of encephalitozoonosis have been developed (Croppo et al., 1998; Franzen et al., 1998; Weiss and Vossbrinck, 1998) . PCR can be performed on the intestine, brain, heart, liver, lung, or kidney tissue with a good (86%) overall detection rate reported (Leipig et al., 2013) .

Differential Diagnoses If the animals are demonstrating motor paralysis, conditions such as splay leg should be considered. For neurological signs, consider bacterial meningitis due to P. multocida infection or rabbit hemorrhagic disease.

Treatment, Prevention, and Control Prevention and control of the organism in the colony are done by elimination of the organism from the colony of infected rabbits. Because this is a latent disease in rabbits, serologic methods must be used to identify carriers of the organism. The indirect fluorescence antibody test has LABORATORY ANIMAL MEDICINE been used successfully to identify infected rabbits (Cox, 1977) . The elimination of infected rabbits must be accompanied by disinfection of the environment. Several disinfectants have been effective against this organism. Encephalitozoon was killed by 2% (v/v) Lysol, 10% (v/v) Formalin, and 70% (v/v) ethanol (Shadduck and Polley, 1978) 1% hydrogen peroxide, and 1% sodium hydroxide (Kunzel and Joachim, 2010) .

Successful treatment and prevention of E. cuniculi in the rabbit has been reported with use of fenbendazole (Suter et al., 2001) . For cases of phacoclastic uveitis, removal of the lens is the treatment of choice (Kunzel and Joachim, 2010) .

Research Complications Encephalitozoonosis is most commonly subclinical disease, which makes it difficult to determine the effects it may have on research. Granulomatous reactions would complicate renal physiology and neurologic research. Depression of the IgG response and an increase in the IgM response to Brucella abortus antigens has been demonstrated in rabbits infected with Encephalitozoon organisms (Cox, 1977) .

Encephalitozoonosis is also a recognized disease in immunodeficient humans. It is recommended that such individuals seek medical counsel prior to handling rabbits. Isolates from humans have been shown to be infectious for rabbits (Mathis et al., 1997) .

Etiology Psoroptes cuniculi is a nonburrowing mite and the causative agent of psoroptic mange, also called ear mange, ear canker, or otoacariasis. The organism is distributed worldwide, but with modern husbandry practices, it is mostly historical in laboratory rabbit colonies (Schoeb et al., 2007) .

Clinical Signs Lesions occur primarily in the inner surfaces of the external ear. The lesions are pruritic and can result in scratching, head shaking, pain, and even self-mutilation (Hofing and Kraus, 1994) . A tan, crusty exudate accumulates in the ears over the lesions and can become quite extensive and thick (Fig. 10.5) . The skin under the crust is moist and reddened. The ears may become malodorous.

Epizootiology All stages of the mite (egg, larva, protonymph, and adult) occur on the host. Early in the infestation, mites feed on sloughed skin cells and lipids. As local inflammation increases, they ingest serum, hemoglobin, and red blood cells (Deloach and Wright, 1981; Hofing and Kraus, 1994) . The entire life cycle is complete in 21 days. Mites are relatively resistant to drying and temperature and can survive off the host for 7-20 days in a temperature range of 5-30°C and relative humidity of 20-75%.

Pathology Lesions are characterized histologically by chronic inflammation, hypertrophy of the Malpighian layer, parakeratosis, and epithelial sloughing. A hypersensitivity response to the mites, mite feces, and saliva likely contributes to lesions (Hofing and Kraus, 1994) .

Diagnosis Mites are large enough to be seen with the unaided eye or with an otoscope. Material scraped from the inner surface of the ear can also be examined using a dissecting microscope. Mites are oval-shaped with well-developed legs that project beyond the body margin. Adult males measure 431-547 μm × 322-462 μm, and females measure 403-749 μm × 351-499 μm (Hofing and Kraus, 1994) .

Differential Diagnoses Rarely, infection with Sarcoptes scabiei or Cheyletiella parasitovorax should be considered as differential diagnoses.

Treatment, Prevention, and Control Several successful treatments have been reported. Prior to local treatment, the ears should be cleaned gently to remove accumulated exudate. One treatment involves the application of 3% rotenone in mineral oil (1:3) every 5 days for 30 days. Ivermectin is an effective treatment at dosages of 400-440 μg/kg SC or IM (Curtis et al., 1990; McKellar et al., 1992; Wright and Riner, 1985) . One or two doses were utilized for effective treatment. Treatment of moderate to severe infestations with ivermectin alone can fail. Using adjunct vitamin therapy to minimize oxidative tissue damage has been shown to enhance treatment success (Singh et al., 2012) . A single dose of topical selamectin at a minimum of 6 mg/kg selamectin (Kurtdede et al., 2007) and a single injection of LABORATORY ANIMAL MEDICINE eprinomectin at 200 or 300 μg/kg (Pan et al., 2006) were found to be effective treatments. Regardless of treatment modality, it is generally recommended that the entire group of rabbits be treated at the same time. Heat (40°C) and desiccation (<20% humidity) will kill parasites that are not on the host (Arlain et al., 1984) .

Vaccine targets have been investigated, with gut surface antigen being the primary focus (Rossi et al., 2007) .

Research Complications P. cuniculi has been associated with immune suppression and a systemic inflammatory reaction (Shang et al., 2014) . Ear trauma secondary to Psoroptes infestation can limit access to the auricular artery and veins.

2. Cheyletiella spp. (C. parasitovorax, C. takahasii, C. ochotonae, C. johnsoni)

Etiology Cheyletiella mites are nonburrowing skin mites of rabbits. They are distributed worldwide. Several closely related species have been reported to occur on rabbits, namely, C. parasitovorax, C. takahasii, C. ochotonae, and C. johnsoni (Hofing and Kraus, 1994) .

Clinical Signs The anatomic site most commonly infested is the area over the scapulae. There may be mild hair loss in the area, and the skin may have a gray-white scale (Cloyd and Moorhead, 1976) . Affected rabbits do not scratch, and there is no evidence of pruritus. Skin lesions are mild or nonexistent.

Epizootiology All stages (egg, larva, pupa, and adult) in the life cycle occur on the host. Mites remain in association with the keratin layer of the skin and feed on tissue fluid (Myktowycz, 1957) . Transmission is probably by direct contact (Schoeb et al., 2007) .

Pathology When present, skin lesions are characterized by mild dermatitis, hyperkeratosis, and an inflammatory cell infiltrate (Hofing and Kraus, 1994) .

Diagnosis Mites can be isolated by scraping or brushing fur in the affected areas onto a slide. Clearing samples with 5-10% potassium hydroxide will improve visibility of the mites, which can then be identified using a dissecting microscope. The female measures 450 × 200 μm, and the male is 320 × 160 μm. Cheyletiella mites have a large, distinctive curved claw on the palpi (Pegg, 1970) .

Differential Diagnoses Other skin mites (such as Sarcoptes scabei) or fur mites (Leporacarus gibbus) that can affect rabbits should be considered as well as the possibility of dermatophytosis.

Treatment, Prevention, and Control Topical acaricides are often used and are effective at controlling infestation. Ivermectin (subcutaneous or subcutaneous and oral) and selamectin (topical) treatments have been used successfully. Eggs in the environment can reinfest the host, so posttreatment environmental sanitation is important (Mellgren and Bergvall, 2008) .

Research Complications Cheyletid mites can cause a transient dermatitis in humans who are in close contact with infested animals (Cohen, 1980; Lee, 1991) . For this reason, these mites can be considered a zoonotic pathogen.

Etiology Sarcoptes scabiei is a burrowing mite and the causative agent of sarcoptic mange. Mites of the genus Sarcoptes are generally considered to be one species, S. scabiei, but are often further identified by a variety name corresponding to the host species (e.g., S. scabiei var. cuniculi). The organisms are commonly referred to as itch or scab mites. The disease has a worldwide distribution.

Clinical Signs Affected rabbits will exhibit intense pruritus with hair loss and abrasions as a resulting from scratching. Serous encrustations on the skin and secondary bacterial infections are common. There has been one report of a secondary infection with the yeast Malassezia (Radi, 2004) . Anemia and leukopenia can also be observed in affected rabbits (Arlain et al., 1988) .

Epizootiology Sarcoptic are similar to notoedric mites (Notoedres cati) in morphology, life cycle, and public health significance. Mites burrow and produce an intensely pruritic dermatitis. Lesions are most common on the head (Hofing and Kraus, 1994) .

All stages of sarcoptic mange mites occur on the host. The females burrow into the skin to lay eggs. Young larvae can also be found in the skin, whereas older larvae, nymphs, and males reside on the skin surface. Mites feed on lymph and epithelial cells (Hofing and Kraus, 1994) .

Pathology Amyloidosis of the liver and glomerulus have been reported in rabbits with severe infestation (Arlain et al., 1990) . The skin itself is hyperplastic and hyperkeratotic, with inflammatory response evident in the dermis (Schoeb et al., 2007) .

Diagnosis Because Sarcoptes is a burrowing mite, skin scrapings are necessary to diagnose infestation. Samples may be cleared with 5-10% potassium hydroxide. Female mites measure 303-450 μm × 250-350 μm. The body shape is round, and the legs are very short.

Differential Diagnoses Other causes of dermatitis in rabbits (such as Cheyletiella spp., P. cuniculi or dermatophytosis) should be considered.

Ivermectin is effective at eliminating infestation at 100 μg/kg administered subcutaneously. A single topical dose of selamectin at 10-12 mg/kg reduced the number of mites found on skin scrapings of Angora rabbits (Kurtdede et al., 2007) and eliminated clinical signs and parasitic infestation in a group of mixed-breed rabbits at a dose of 30 mg/rabbit (Farmaki et al., 2009) . As with Psoroptes, more 'natural' treatments are being investigated with good preliminary results from eugenol (Pasay et al., 2010) and Eupatorium spp. (Nong et al., 2013) .

Research Complications No specific research complications have been reported. Sarcoptes can cause a selflimiting dermatitis in humans.

A wide variety of arthropod parasites has been reported in wild rabbits but they are extremely rare in laboratory rabbits. For an extensive listing the reader is referred to other sources (Hofing and Kraus, 1994) .

Etiology Historically, the rabbit pinworm was identified as Oxyuris ambigua, but is now known as Passalurus ambiguus (Hofing and Kraus, 1994) .

Clinical Signs Even when rabbits have heavy oxyurid burdens, clinical signs are not usually apparent (Erikson, 1944; Soulsby, 1968 ). One case report described unsatisfactory breeding performance and poor condition in a rabbit colony infested with the parasite.

Epizootiology P. ambiguus has a direct life cycle. Mature pinworms are found in the lumen of the cecum or colon of the rabbit. After ingestion, the eggs hatch in the small intestine, and the larvae molt with maturation in the cecum. The prepatent period is between 56 and 64 days (Taffs, 1976) .

Transmission occurs easily via ingestion, given that individual rabbits have been found with over 1000 adult parasites (Hofing and Kraus, 1994) and that embryonated eggs pass out in the feces and are immediately infective (Schoeb et al., 2007; Taffs, 1976) .

Pathology Minimal to no lesions are associated with this pinworm (Schoeb et al., 2007) .

Diagnosis Eggs can be found in feces, cecum, or colon.

Differential Diagnoses This is the only reported pinworm in rabbits and it is not known to cause lesions or disease.

Treatment, Prevention, and Control Several successful treatment strategies for rabbit oxyuriasis have been reported. Piperazine citrate at 100 mg/100 ml of drinking water for 1 day was successful in eliminating infestation (Hofing and Kraus, 1994) . At 25 and 50 ppm, fenbendazole mixed in the food for 5 days eliminated all immature and adult pinworms (Duwell and Brech, 1981) . Subcutaneous doses of ivermectin (0.4 mg/kg) were reported to be ineffective in reducing the burden of Passalurus organisms in field populations of snowshoe hares (Lepus americanus) (Sovell and Holmes, 1996) . Due to the direct life cycle, strict husbandry and sanitation practices are required to prevent introduction and spread throughout a rabbit colony (Schoeb et al., 2007) .

Research Complications None have been described.

Etiology Dermatophytosis, also known as ' ringworm' or 'tinea', refers to a skin infection caused by a dermatophyte, a keratinophilic and keratinolytic fungus (Chermette et al., 2008; Mendez-Tovar, 2010; Robert and Pihet, 2008) . Dermatophytes are a group of closely related filamentous fungi that are able to invade the stratum corneum of the epidermis and keratinized tissues including the skin, nail, and hair (Kanbe, 2008) . Dermatophytes can infect various animal species, including humans, and the disease is considered contagious and zoonotic (Cafarchia et al., 2012b; Chermette et al., 2008; Kramer et al., 2012) . The zoophilic dermatophytes Trichophyton mentagrophytes and Microsporum canis infect rabbits (Cafarchia et al., 2010 (Cafarchia et al., , 2012a Chermette et al., 2008; Kramer et al., 2012) .

Clinical Signs The general presentation of dermatophytosis in animals is an area of circular alopecia with erythematous margin and thin desquamation (Chermette et al., 2008) . Pruritus is generally absent and lesions can be single or multiple (Chermette et al., 2008) . Although lesions can be localized in any region, the anterior part of the body and the head seem to be more frequently involved (Chermette et al., 2008) . In rabbits, lesions are often found on the ears and the face (around the eyes and on the nose) and these lesions show scaling and crusting (Chermette et al., 2008; Kramer et al., 2012) . Infected rabbits may not exhibit clinical signs and may serve as carriers (Balsari et al., 1981; Cafarchia et al., 2010 Cafarchia et al., , 2012a Chermette et al., 2008; Lopez-Martinez et al., 1984) .

Epizootiology Although dermatophytosis is a common cutaneous disease of rabbits and other animals, its incidence is low in well-managed laboratory animal facilities (Chermette et al., 2008; Connole et al., 2000) . Contact with infected animals or contaminated environments represent the major risk of infection (Chermette et al., 2008) . Young or immunocompromised rabbits are more susceptible (Connole et al., 2000; Kramer et al., 2012) . On rabbit farms, the occurrence of lesions, the age of the rabbits, and farm management practices were identified as the most significant risk factors for the occurrence of dermatophytosis (Cafarchia et al., 2010) .

Clinically, disease expression varies depending on the host, fungal species, and enzyme production (Cafarchia et al., 2012a; Vermout et al., 2008) . The pathogenesis involves contact, adherence, germination, invasion, and penetration (Cafarchia et al., 2012a; Mendez-Tovar, 2010; Vermout et al., 2008) . These stages can be associated with the secretion of enzymes that degrade the infected tissue components (Cafarchia et al., 2012a) . T. mentagrophytes isolates from rabbits with skin lesions showed a significantly higher elastase and gelatinase activity compared LABORATORY ANIMAL MEDICINE to isolates from clinically unaffected rabbits and from the environment (Cafarchia et al., 2012a) . Furthermore, M. canis isolates from rabbits with skin lesions showed a significantly higher lipase activity compared to isolates from clinically unaffected rabbits and from the environment (Cafarchia et al., 2012a) .

Pathology Histopathologic changes consist of mild to severe dermatitis.

Diagnosis The Wood's lamp (ultraviolet light) method and direct examination of hairs and scales are fast and affordable tests (Chermette et al., 2008; Robert and Pihet, 2008) . The Wood's lamp can be used to screen for infections caused by M. canis (Chermette et al., 2008) . M. canis-infected hairs fluoresce with an apple-green color and can be collected for microscopic examination and culture (Chermette et al., 2008) . The results of the Wood's lamp examination should be systematically confirmed by direct examination of hairs and/or fungal culture (Chermette et al., 2008) . Deep skin scraping should be performed to obtain hair and scales and confirm the absence of ectoparasites such as mites that can be associated with dermatophytosis (Cafarchia et al., 2010; Chermette et al., 2008) . Clearing solutions such as chlorolactophenol or 10% potassium hydroxide (KOH) can then be used to digest keratin prior to microscopic examination (Chermette et al., 2008; Robert and Pihet, 2008) . The surface of the hair typically demonstrates clusters or chains of arthroconidia (Chermette et al., 2008) . Giemsa-stained skin scrapings allow observation of the arthroconidia along the hair (Chermette et al., 2008) .

Fungal culture is the 'gold standard' for the diagnosis of dermatophytosis and the only method for the phenotypic identification of dermatophyte species (Chermette et al., 2008) . The fungal culture must be complemented with direct examination of samples for optimal interpretation of the results (Chermette et al., 2008; Robert and Pihet, 2008) . Samples for fungal culture may include hairs, scales, crusts, skin scrapes, and tissue biopsies (Chermette et al., 2008) . Samples that are obtained from the margin of new skin lesions enhance fungal recovery by culture (Chermette et al., 2008) . A brush can also be impressed on the surface of the culture medium after combing the fur and obtaining fungal spores with hair and debris (Robert and Pihet, 2008) . Two media that can be used for fungal culture include Sabouraud dextrose agar (supplemented with cycloheximide and antibiotics) and Dermatophyte Test Media (DTM) (Chermette et al., 2008; Robert and Pihet, 2008) . If histological examination is performed, periodic acid Schiff (PAS), or methylamine silver stain can be used to detect arthroconidia and hyphae (Chermette et al., 2008) . Molecular methods to identify dermatophytes have also been described and include PCR-RFLP and sequencing of the internal transcribed spacer (ITS) region (Chermette et al., 2008; Kanbe, 2008; Robert and Pihet, 2008) . Specific identification of the dermatophyte is essential for a better understanding of the epidemiology and prevention of the disease (Chermette et al., 2008) . Differential Diagnoses The differential diagnoses can include other dermatoses caused by bacteria or ectoparasites (Cafarchia et al., 2010; Chermette et al., 2008) .

Treatment, Prevention, and Control Dermatophytosis is considered a self-limiting disease in immunocompetent animals (Chermette et al., 2008) . However, rabbits with dermatophytosis should be culled or separated from a laboratory animal colony due to the contagious and zoonotic nature of the disease (Chermette et al., 2008) .

The best method to prevent dermatophyte infection is to prevent contact with infected animals and contaminated environments including fomites (Chermette et al., 2008) . An animal that contacts an infected animal or a contaminated environment can be washed with antifungal shampoo (Chermette et al., 2008) . Two vaccines incorporating live attenuated cells of T. mentagrophytes have been used to prevent disease in rabbits and other animals (Lund and Deboer, 2008) . The Mentavak vaccine is from Russia and the Trichopelen vaccine (http://www. bioveta.cz/en/veterinary-division/home/) is from the Czech Republic (Lund and Deboer, 2008) . Trichopelen is also indicated for treatment of dermatophytosis (Lund and Deboer, 2008) .

Enzootic dermatophytosis may be the result of the high resistance of the arthroconidia in the environment, the number of host species involved, and the close confinement of animals (Chermette et al., 2008) . Isolation or culling of infected animals plus environmental and equipment disinfection are required to control this disease (Chermette et al., 2008) . A 1:10 dilution of household bleach or a 0.2% enilconazole solution can be used to disinfect the environment (Chermette et al., 2008) . Infected animals should be handled with care to avoid zoonotic transmission (Chermette et al., 2008) .

If treatment is elected, antifungal treatment shortens the course of the infection and reduces dissemination of arthroconidia to other animals and into the environment (Chermette et al., 2008) . Systemic and topical antifungal treatment can be used in combination (Chermette et al., 2008) . Systemic drugs include griseofulvin (gold standard) or azole derivatives such as itraconazole (Chermette et al., 2008; Vella, 2013) . It is important to know that these drugs can have side effects and be contraindicated due to their teratogenic potential (Chermette et al., 2008) . Topical treatment may include 0.2% enilconazole, a combination of 2% miconazole and 2% chlorhexidine, or lime sulfur (Chermette et al., 2008; Vella, 2013) . Treatment can be discontinued after two negative fungal culture results (Chermette et al., 2008) .

Research Complications Dematophyte lesions could confound histological studies involving the skin (Connole et al., 2000) .

Etiology Pneumocystosis in rabbits is caused by the fungus Pneumocystis oryctolagi (Dei-Cas et al., 2006) .

Clinical Signs Infected rabbits may not develop clinical signs, but immunocompromised hosts can develop severe interstitial pneumonitis (Dei-Cas et al., 2006; Sheldon, 1959) .

Epizootiology Corticosteroid treatment can induce disease in infected rabbits; however, spontaneous disease (not associated with drug treatment) can also occur (Dei-Cas et al., 2006; Sheldon, 1959; Soulez et al., 1989) . P. oryctolagi is transmitted through the transplacental route (Cere et al., 1997a; Sanchez et al., 2007) and through direct contact and aerosolization (Cere and Polack, 1999; Cere et al., 1997b; Hughes, 1982; Wakefield, 1994 Wakefield, , 1996 . Spontaneous pneumocystosis can occur at weaning, evolves during 7-10 days, and induces lung lesions and blood biochemical profile changes (Dei-Cas et al., 2006; Soulez et al., 1989) . The organisms attach specifically to Type 1 epithelial alveolar cells and proliferate, filling up pulmonary alveoli cavities leading to respiratory failure (Dei-Cas et al., 2006) . Changes in surfactant appear to be necessary for Pneumocystis proliferation (Prevost et al., 1997) . Pneumocystis colonization decreases and becomes very low in 60-day-old rabbits (Dei-Cas et al., 2006) . Most rabbits recover from pneumocystosis within 3-4 weeks (Dei-Cas et al., 2006) . The spontaneous resolution of pneumocystosis in rabbits may be associated with expression of interferon gamma (Allaert et al., 1997) . Immunosuppression may be suspected in cases of severe pulmonary disease associated with spontaneous pneumocystosis (Sheldon, 1959) .

Pathology Histologically, cystic forms of the organism can be detected in the lungs using toluidine blue O (TBO), GMS, or PAS stains (Dei-Cas et al., 2006) . Interstitial thickening of alveolar septa and increased numbers of Type 2 epithelial alveolar cells are characteristic of this infection (Creusy et al., 1996) .

Diagnosis For diagnosis, samples from nasal cavity wash, or post-mortem, from terminal bronchoalveolar lavage (BAL) or lung homogenates can be used for Pneumocystis detection by nested PCR (Dei-Cas et al., 2006; Tamburrini et al., 1999; Wakefield, 1996) . Serological diagnosis can also be performed (Tamburrini et al., 1999) . Lung impression smears, lung-homogenate smears, and BAL fluid samples can be stained for microscopic detection of Pneumocystis (Dei-Cas et al., 2006) . Useful stains include TBO, Gomori-Grocott's methenamine silver nitrate (GMS), and methanol-Giemsa or Giemsalike stains (Dei-Cas et al., 2006) . Other useful detection methods include phase-contrast microscopy and the use of Pneumocystis-specific fluorescein-labeled antibodies (Dei-Cas et al., 2006) . Differential Diagnoses P. multocida can induce respiratory disease in rabbits and can be included in the differential diagnoses.

Treatment, Prevention, and Control For prevention, new rabbits should be negative for Pneumocystis. Cotrimoxazole treatment and nested PCR have been used as a screening mechanism to eliminate Pneumocystis from colony-maintained rabbits (Cere et al., 1997c) . Decontamination practices and air filtration were also important for eradication (Cere et al., 1997c) . Confirmation of a Pneumocystis-free status in a rabbit colony was demonstrated by negative PCR results and/ or failure to induce pneumocystosis after experimental corticosteroid challenge (Dei-Cas et al., 2006) .

Research Complications Research studies may be affected if rabbits of unknown Pneumocystis status are experimentally treated with corticosteroids or other immunosuppressant drugs (Sheldon, 1959) . Pulmonary lesions may be found in infected rabbits and could potentially confound respiratory research studies (Sheldon, 1959) .

Etiology Unknown. Clinical Signs Trichobezoar is often subclinical. If the trichobezoar causes partial or complete blockage, clinical signs of gastric or intestinal obstruction will result. Death can occur due to prolonged anorexia and metabolic imbalances (Gillett et al., 1983 ). It appears that obstruction of the pylorus, and not the volume of the gastric mass, is the critical factor in determining the clinical progress of the animal (Leary et al., 1984) .

Epizootiology The condition occurs sporadically in rabbit colonies.

Pathology The discovery of a hairball in a rabbit is often an incidental finding during necropsy. Up to 21% of rabbits have been found to have gastric trichobezoars during routine necropsy (Leary et al., 1984) . Gastric rupture can also result from an obstructive trichobezoar (Gillett et al., 1983) .

Diagnosis Diagnosis is often difficult because the clinical signs are nonspecific and the disease often progresses gradually. Some cases involving acute pyloric obstruction result in sudden clinical disease and rapid clinical decline of the animal. Manual palpation may indicate the presence of a firm mass in the cranial abdomen. Gastric radiographs using contrast media may aid in the diagnosis, but definitive diagnosis is often made during exploratory surgery (Gillett et al., 1983) .

Differential Diagnoses Constipation and intestinal foreign body should be considered in the differential list.

Treatment, Prevention, and Control Treatment of trichobezoar is often unsuccessful. Oral administration of mineral oil at 10 ml/day has been reported (Suckow and Douglas, 1997) . Alternatively, oral administration of 5-10 ml of fresh pineapple juice daily has been reported as a possible treatment modality (Harkness and Wagner, 1995) . If medical treatment does not resolve the condition, a gastrotomy should be performed. Early surgical intervention is important in such cases, as other, subsequent metabolic abnormalities may quickly increase the surgical risk to the rabbit (Bergdall and Dysko, 1994) .

Research Complications None have been reported.

Etiology Subluxation or compression fractures of lumbar vertebrae are often secondary to struggling during restraint, particularly when the hindquarters of the rabbit are not supported (Bergdall and Dysko, 1994) . The seventh lumbar vertebra (L7) or its caudal articular processes are considered the most frequent sites of fractures, with fracture occurring more commonly than dislocation (Flatt et al., 1974) .

Clinical Signs Clinical signs include posterior paresis or paralysis, loss of sensation in the hindlimbs, urinary and/or fecal incontinence, and perineal staining.

Pathology Spinal cord hemorrhage and necrosis can be found.

Diagnosis Diagnosis is based on clinical signs, history of recent restraint, struggling or other trauma, and palpation or radiographic analysis of the vertebral column.

Differential Diagnoses Spinal cord trauma. Treatment, Prevention, and Control Euthanasia of affected animals is usually warranted. Moderate cases (subluxation with spinal edema) may resolve over time. The decision to euthanize should be based on severity of clinical signs. Supportive care includes regular expression of the urinary bladder and prevention and treatment of decubital ulcers. Corticosteroid and diuretic therapy may be effective for cases of subluxation with spinal edema (Bergdall and Dysko, 1994) .

Research Complications Loss of valuable research animals is the primary complication.

Although the condition is often referred to as 'sore hocks,' the correct name is ulcerative pododermatitis. Despite the name, the condition rarely affects the hocks, but rather occurs most frequently on the plantar surface of the metatarsal and, to a lesser extent, the metacarpal regions. The condition is believed to be initiated by wire-floor housing, foot stomping, or having thin plantar fur pads. Poor sanitation may worsen the condition. Solid resting areas on the cage floors are associated with a decreased incidence of ulcerative pododermatitis, whereas a high-energy diet and increased body condition scores are associated with an increased incidence (Sanchez et al., 2012) .

The whole genome sequence from a single female rabbit of the partially inbred Thorbecke rabbit strain was published in 2009 (OryCun2.0; accession AAGW02000000). The annotated assembly is now available at the National Center for Biotechnology Information (NCBI), the University of California Santa Cruz (UCSC), and Ensembl. The rabbit chosen by the Broad Institute for sequencing was obtained from Covance in 2004. The assembly has 2.24 Gbp in 21 autosome and X chromosomes and 489 Mbp in 3219 unplaced scaffolds including mitochondria (Gertz et al., 2013) . The nucleotide sequence of the complete mitochondrial DNA (mtDNA) molecule of the O. cuniculus has been determined (Gissi et al., 1998) . The compositional differences between the two mtDNA strands have also been detailed (Gissi et al., 1998) .

The sequencing of the rabbit genome, understanding of rabbit reproduction, and advances in genetic manipulation in the mouse production colonies have led to the ability to produce genetically engineered rabbits. The rabbit offers an alternative model when size or tissue characteristics of a genetically modified mouse are not appropriate. These genetic manipulation techniques were first described by Robl (Robl and Burnside, 1994) . Additional methods have been developed and include pronuclear injection of single cell embryos, injection of genetically modified embryonic stem cells into blastocysts, sperm-mediated gene transfer, and genetically modified somatic cell and nuclear transfer (Christensen and Peng, 2012) . Commercial companies have been formed to provide genetic modification services with emphasis on production of a unique protein in the milk of rabbits.

This section will outline spontaneous hereditary conditions of the rabbit that have been well characterized. Some conditions represent conditions that have been identified in humans and other conditions offer insight into the mechanism(s) of particular organ or immune function.

Hydrocephalus refers to dilatation of the cerebral ventricles and is usually accompanied by accumulation of cerebrospinal fluid within the dilated spaces. Some cases of hydrocephalus in rabbits have been presumed to be related to a single autosomal recessive gene (hy/hy); however, occurrence with other abnormalities suggests that inheritance may be more complicated (Lindsey and Fox, 1994) . In some cases, the condition appears to be inherited along with various ocular anomalies as an autosomal gene with incomplete dominance. Hydrocephalus may also occur in rabbits as a congenital condition related to hypovitaminosis A in pregnant does (Lindsey and Fox, 1994) .

Etiology Buphthalmia is inherited as an autosomal recessive trait, although penetrance is presumably incomplete since severity and the age of onset vary greatly and some bu/bu individuals do not develop buphthalmia (Hanna et al., 1962) .

Clinical Signs Rabbits with hereditary glaucoma develop ocular changes that resemble human congenital glaucoma and buphthalmia. Newborn bu/bu rabbits initially have normal intraocular pressure (IOP; 15-23 mmHg) but increased pressures of 26-48 mmHg may develop after 1-3 months of age (Burrows et al., 1995; Knepper et al., 1997) . The eyes become progressively buphthalmic (either uni-or bilaterally) but the IOP can return to normal or to sub-normal levels after 6-10 months. Typical clinical changes include increased corneal diameter as the globe enlarges because the sclera is still immature. The cornea may develop a cloudy or bluish tint, corneal edema, increased corneal vascularity, and flattening of the cornea. Structural changes may include widening of the angle, thickening of Descmet's membrane, atrophy of the ciliary process, and excavation of the optic disk. Impaired aqueous outflow may be due to incomplete cleavage of the drainage angle with abnormal insertion of uveal tissue into the cornea (Tesluk et al., 1982) . In some cases, the cornea ulcerates and ruptures.

There is also a marked reduction in semen concentration in buphthalmics, with a decrease in libido and decreased spermatogenesis in affected males (Fox et al., 1969) .

Epizootiology The condition is common in New Zealand White rabbits.

Pathology By 2 weeks of age, the morphology of the congenital glaucoma trabecular network becomes abnormal with a smaller entrance to the trabecular network at the iris base, smaller intertrabecular openings within and between the trabecular lamellae, and by 6 weeks, iris pillars with extensive lateral extensions in the angle recess can be observed. Most intertrabecular spaces remain open; however, the inner intertrabecular spaces adjacent to the aqueous plexus become compressed.

Diagnosis Diagnosis is based on clinical signs and measurement of intraocular pressure.

Treatment, Prevention, and Control Specific treatment of buphthalmia has not been described for rabbits; however, affected individuals should not be used for breeding purposes.

Research Complications Loss of valuable research animals is the primary complication.

Etiology Mandibular prognathism is the most common inherited disease of domestic rabbits. The condition is inherited as an autosomal recessive trait (mp/mp) with incomplete penetrance (Fox and Crary, 1971; Huang et al., 1981; Lindsey and Fox, 1994) .

Clinical Signs Malocclusion related to mandibular prognathia may be clinically apparent as early as 2-3 weeks of age, but is more typically seen in older rabbits post weaning. Clinical signs may include anorexia and weight loss. If severe enough and left untreated, affected animals will starve since they cannot properly prehend and masticate food.

Epizootiology Normally, the lower incisors occlude with the large upper incisors, as well as with a pair of small secondary incisors that are immediately caudal to the primary maxillary incisors. The lower set of incisors typically wear against the upper set during normal biting activity, along an arc formed by biting movements of the lower incisors, whereas the maxillary secondary incisors wear at right angles to the mandibular incisors. The incisors wear more quickly at the posterior aspect in rabbits, partly because the enamel layer is thinner on that side. Affected rabbits have a normal dental formula.

The specific abnormality associated with mandibular prognathism is that the maxilla is short relative to a mandible of normal length. Thus, although the mandible appears abnormally long, the primary defect involves the maxilla. In rabbits, the teeth (including the molars and premolars) grow continuously throughout life. The incisors, for example, grow at the rate of 2.0-2.4 mm/ week. When occlusion is normal, the teeth wear against one another and in this way remain a normal length. However, when occlusion is abnormal because of conditions that include mandibular prognathia, the teeth may become greatly elongated because typical attrition of the incisors does not occur. In affected animals the lower incisors often extend anterior to the upper incisors and protrude from the mouth, whereas the upper primary incisors grow past the lower incisors and curl within the mouth. In some instances, the upper incisors curl around dorsally and lacerate the mucosa of the hard palate. Secondary infection and abscessation may occur in such cases.

Diagnosis Diagnosis is based on clinical signs. Differential Diagnoses Malocclusion secondary to mandibular or maxillary fracture should be considered.

Treatment, Prevention, and Control Overgrown teeth should be trimmed every 2-3 weeks or more frequently if needed. Trimming is preferably performed with a dental bur to avoid cracking the tooth, which LABORATORY ANIMAL MEDICINE may happen more frequently if a bone or wire cutter is used. Care should be taken to avoid exposing the pulp cavity as the result of excessive trimming. Because the condition is hereditary, use of affected animals as breeding stock should be avoided.

Research Complications No specific research complications have been reported.

A number of disorders characterized clinically by complete abduction of one or more legs and the inability to assume a normal standing position are described by the term 'splay leg'. Young kits of 3-4 weeks of age are most commonly affected. Affected rabbits cannot adduct limbs and have difficulty in making normal locomotory movements. Most commonly, animals are affected in the right rear limb, although the condition may be uni-or bilateral and may affect the anterior, posterior, or all four limbs. Rabbits with splay leg may have difficulty in accessing food and water; thus, attention to adequate nutrition is required as part of proper clinical care.

The clinical signs of splay leg may be due to an overall imbalance of development of the neural, muscular, and skeletal systems. Possibly, some animals compensate with torsion and exorotation of the limb at the hip, whereas rabbits that are unable to compensate are clinically affected.

Although the precise pathogenesis of splay leg is not entirely understood, at least some cases are ascribed to inherited disorders. Typical clinical signs are secondary to femoral endotorsion, with a shallow acetabulum but without luxation of the femur at the hip. The semitendinosus muscle of affected animals is abnormal, with smaller fibers and abnormal mitochondria. Some reports suggest that the condition is associated with inherited achondroplasia of the hip and shoulder, whereas others indicate that a recessively inherited anteversion of the femoral head can be involved.

Self-mutilating behavior in a Checkered cross (cross between English Spot, German Checkered Giant, and Checkered of Rhineland rabbits) was reported to occur as an inherited trait (Iglauer et al., 1995) . Autotraumatization of the feet and pads was observed. The abnormal behavior could be interrupted by administration of haloperidol.

Although not manifested as a disease, the presence of serum atropine esterase allows rabbits to inactivate atropine when administered for therapeutic purposes (Liebenberg and Linn, 1980; Stormont and Suzuki, 1970) .

The enzyme also permits rabbits to consume diets containing belladonna compounds.

The enzyme is produced by a semidominant gene Est-2F. Three phenotypes are recognized depending on the number of genes expressed. The enzyme first appears in the serum at 1 month of age, and enzyme levels are greater in females than in males (Lindsey and Fox, 1994) . The Est-2F gene is linked to genes controlling the black pigment in the coat (Forster and Hannafin, 1979; Fox and van Zutphen, 1977; Sawin and Crary, 1943) .

Hereditary deficiency of the third component of complement (C3) was found in a strain of rabbits. This same strain also exhibited a hereditary C8 alpha-gamma deficiency. The serum C3 concentration, hemolytic C3 activity, and total complement hemolytic activity of these animals were significantly reduced. The low level of serum C3 in these rabbits was not due to C3 conversion, partial C3 antigenicity, and presence of a C3 inhibitor or hypercatabolism of normal C3. The C3 deficiency was transmitted as a simple autosomal co-dominant trait. Rabbits with this trait have a lower survival at 3 months than normal rabbits (Komatsu et al., 1988) .

This complement deficiency syndrome in the rabbit has been well characterized. This syndrome was initially reported in 1964 in a strain of rabbits that lacked the sixth component of the hemolytic complement system (Rother et al., 1966) . Whole blood clotting time in glass or plastic was prolonged and prothrombin consumption was decreased in blood from the deficient animals. Other parameters of blood coagulation were normal, including prothrombin time, partial thromboplastin time, specific clotting factor activities, platelet factor III function, platelet count, and bleeding time (Zimmerman et al., 1971) . Abnormal platelet response is also characteristic of this syndrome in the rabbit (Lee et al., 1974) . Complement C6-deficient rabbits are protected against diet-induced atherosclerosis despite having similar profiles in cholesterol levels and plasma lipoprotein. When compared to normal rabbits, differences in atherosclerotic plaque formation were discernible macroscopically, with extensive aortic lesions being visible in all normal rabbits while absent in all C6-deficient animals (Schmiedt et al., 1998) . The inheritance pattern for this defect is autosomal recessive (Abe et al., 1979) .

A progressive neurological syndrome has also been observed in the C6-deficient rabbits. This syndrome is clinically characterized by subacute motor neuropathy. Pathological studies of affected animals revealed (1) severe axonal degeneration in the sciatic nerve involving mainly motor fibers; (2) occasional peripheral axonal enlargement closely associated with axonal LABORATORY ANIMAL MEDICINE degeneration; (3) presence of structured abnormal material in normal-size myelinated fibers of the central and peripheral nervous systems; and (4) widespread occurrence of dystrophic axons and axonal spheroids in the gray matter of the central nervous system. By ultrastructural examination, dystrophic axons were filled with tubulovesicular material, appearing as stalks of parallel membranes and dense bodies similar to what is described in human neuroaxonal dystrophies (NAD). The disease manifested by C6-deficient rabbits may represent an animal model of primary human NAD (Giannini et al., 1992) .

Genetic deficiency of the alpha-gamma-subunit of the eighth complement component (C8 alpha-gamma) was found in a substrain of the New Zealand White rabbits. The serum of this deficient rabbit lacked the immunochemical and functional alpha-gamma-subunit of C8 (C8D). This syndrome is transmitted as a simple autosomal recessive trait. The syndrome is characterized by smaller body weight compared to those of heterozygous and normal rabbits. In addition, survival rates for the first 3 months of life of the deficient animals tended to be lower than those of heterozygous and normal littermates (Komatsu et al., 1985) . All C8D rabbits (more than 180 animals obtained thus far) were consistently smaller than normal littermates from birth to adulthood, i.e., 86% of normal size at birth, 57% of normal size at 35 days of age, and 68% of normal size at adulthood. The C8α-γ deficiency in rabbits is always associated with dwarfism. Furthermore, there appears to be a discrete recessive dwarf gene (dw-2), whose locus is not linked to C8D. Rabbits double-homozygous for C8D and dw-2 (severe dwarf) were smaller than the C8D or dwarf rabbits and almost all of the severe dwarf rabbits died within 35 days after birth. The actual and relative weights of the thymus in the C8D rabbits were consistently lower than those of normal rabbits, but histological examination of the C8D thymus did not reveal any abnormalities. The C8D and dwarf rabbits were fertile; however, crosses of C8D females with C8D or dwarf males led to a reduced delivery rate and small litter size. The C8D locus is loosely linked to the C3 hypocomplementemic locus (C3-hypo) (map distance 24 cM) but not to the hemoglobin blood group locus (Komatsu et al., 1990) .

The inherited characteristics of the Kurosawa and Kusanagi hypercholesterolemic (KHC) rabbit include persistent hypercholesterolemia. This strain of rabbits was produced by inbreeding mutants discovered in 1985. These KHC rabbits had serum cholesterol, triglyceride, and phospholipid levels 8-10 times greater than clinically normal O. cuniculus. The KHC rabbits also had decreased serum high-density lipoprotein cholesterol concentration, about one-third the value in clinically normal rabbits. In addition, the serum lipoprotein electrophoretic patterns were characterized by a strong, broad beta-lipoprotein band and a diminished alphalipoprotein band. Fractionation of lipoprotein lipids revealed increased cholesterol, phospholipid, and triglyceride in the LDL fraction; increased cholesterol and phospholipid in the very LDL fraction; and decreased cholesterol and triglyceride in the high-density lipoprotein fraction. The inheritance is thought to be a single autosomal recessive gene mutation, and analysis of the LDL receptor indicated that the KHC rabbit has a 12-base pair deletion in the LDL receptor mRNA. Macroscopic analysis of the aorta revealed the atheromatous lesions at 2 months of age, drastically increased lesional areas in the total aortic surface at 8 months of age, and a high incidence of coronary atheromas and xanthomas (Kurosawa et al., 1995) .

A spontaneous phenotype in a rabbit was discovered with an elevation of serous lipid ingredients including cholesterol and beta-lipoprotein (beta-LP). Atherosclerotic lesions were evident in the aorta and renal arteries. Nodular xanthomas were also present on the front and rear feet. The HLR strain was inbred to accentuate these characteristics (Watanabe et al., 1977) . The strain was eventually designated the Watanabe-heritable hyperlipidemic rabbit (WHHL-rabbit). An additional report of this strain of rabbits indicated that the WHHL-rabbits spontaneous developed aortic atherosclerosis by 5 months of age and xanthoma of digital joints in 60% of the rabbits aged to 16 months (Watanabe, 1980) .

Historically, spontaneous neoplasia in the laboratory rabbit has not been widely reported because neoplasia in the rabbit is very uncommon before 2 years of age and many laboratory rabbits are not maintained beyond this age (Weisbroth, 1994) . Endometrial adenocarcinoma is the most common tumor in aged female rabbits, with an incidence of 79% reported in a colony of 5-year-old rabbits (Baba and Von Haam, 1972) . Tinkey et al. complied an extensive review of the literature dealing with spontaneous neoplasia in the domestic rabbit. This review contained data on case reports, descriptions of biologic aspects of naturally occurring tumors and reports of experimentally induced tumor models. Neoplasia in Sylvilagus and Lepus were also discussed (Tinkey et al., 2012) .

Uterine adenocarcinoma is by far the most common tumor in rabbits. Typically, the disease is present as multiple tumors and is malignant, often metastasizing to the liver, lungs, and other organs. There is evidence that inheritance plays a role in susceptibility, but parity does not. Uterine leiomyomas and leiomyosarcomas are much less common (Weisbroth, 1994) . There are a few reports of vaginal squamous cell carcinomas (Weisbroth, 1994) and an ovarian hemangioma has been described (Greene and Strauss, 1949) .

Mammary adenocarcinomas are fairly common in older female rabbits and may occur in animals with uterine adenocarcinoma (Weisbroth, 1994) . Papillomas have been described, but mammary adenocarcinomas are much more important. These malignant tumors may metastasize, but the cause of death in affected rabbits is often due to uterine adenocarcinoma. Serial biopsy studies indicate that these tumors are preceded by cystic mastopathy as well as changes in the adrenal and pituitary glands (Greene, 1965) . There may also be small prolactin-secreting pituitary adenomas in rabbits with mammary dysplasia (Lipman et al., 1994) .

Testicular tumors in the rabbit appear to be relatively uncommon. Interstitial tumors are the most common testicular tumor in the rabbit. Seminomas and teratomas have also been reported (Weisbroth, 1994) .

Embryonal nephromas are one of the most common tumors in laboratory rabbits. These tumors are often found incidentally, occur in younger animals, and seldom cause clinical signs (Weisbroth, 1994) . There has been one report of a renal carcinoma in the rabbit (Kaufman and Quist, 1970) and one report of a leiomyoma arising in the urinary bladder (Weisbroth, 1974) .

Malignant lymphomas (lymphosarcomas) are relatively common in rabbits. They may occur in rabbits that are less than 2 years of age (Weisbroth, 1994) , but older rabbits may also be affected. According to (Weisbroth, 1994) , a tetrad of lesions is often seen. These lesions include enlarged kidneys, splenomegaly, hepatomegaly, and lymphadenopathy. Older rabbits have presented with skin nodules and eye lesions; however, malignant lymphomas in the rabbit are seldom leukemic. Most cases of malignant lymphoma appear to resemble the lymphoblastic subtype as seen in humans and mice. Malignant lymphoma is more prevalent in some strains of rabbits than in others, and there is some evidence for a retroviral cause of lymphomas in rabbits (Weisbroth, 1994) . True thymomas (containing both lymphoid and epithelial components) (Vernau et al., 1995) and plasma cell myelomas (Pascal, 1961) are rare in rabbits. One case of myeloid leukemia has been reported (Meier et al., 1972) .

Basal cell tumors are reported to be rare (Weisbroth, 1994) , but they may be underreported (Li and Schlafer, 1992) . Squamous cell carcinomas are also uncommon, and there is no apparent predilection for any particular area of the body (Weisbroth, 1994) . Other cited skin-associated tumors include a trichoepithelioma (Altman et al., 1978) , a sebaceous gland carcinoma (Port and Sidor, 1978) , and two malignant melanomas (Hotchkiss et al., 1994) .

Osteosarcomas are extremely rare in rabbits, and most have arisen in the mandible or maxilla, with only one found in a long bone (Weisbroth, 1994) . No primary tumors arising in cartilage have been described, although some of the reported osteosarcomas have had cartilaginous elements. One tumor of skeletal muscle, a rhabdomyosarcoma, has been reported. A few fibrosarcomas and one fibrosarcoma involving the foot have been reported (Weisbroth, 1994) .

A number of case reports of single tumors are found in the literature. These include a peritoneal mesothelioma (Lichtensteiger and Leathers, 1987) , an intracranial teratoma (Bishop, 1978) , an ependymoma (Kinkier and Jepsen, 1979) , a neurofibrosarcoma, two hemangiosarcomas (Pletcher and Murphy, 1984) , and a malignant fibrous histiocytoma (Yamamoto and Fujishiro, 1989 ). There are a few very old reports of lung tumors dating to the first part of the 20th century (Weisbroth, 1994) .

There are several tumor models in which the cells used for inoculation were originally derived from rabbit tumors. These include the vx-2 carcinoma (Kidd and Rous, 1940) , the Brown Pearce carcinoma (Brown and Pearce, 1923) , and the Greene melanoma (Greene, 1958) . The vx-2 carcinoma originated from a squamous cell carcinoma in a rabbit carrying a Shope papilloma. The most common modern use of this transplantable tumor is as a model for the study of various cancer treatment modalities for metastatic tumors (Stetson et al., 1991) .

The Brown Pearce carcinoma arose from a tumor in a rabbit testis, but the exact tissue of origin of the tumor was never determined. The tumor was readily transplantable and caused stable metastases. Because some tumors regress, even after widespread metastases, this tumor has been used as a model for the study of tumor immunology (Weisbroth, 1994) . The Brown Pearce LABORATORY ANIMAL MEDICINE carcinoma, although extensively characterized and historically used, has been reported in the literature only five times from 1990 to 2009 (Tinkey et al., 2012) .

Hydrometra has been described as a clinical condition of rabbits. All cases were in unmated rabbits that were used experimentally for the production of serum antibodies (Bray et al., 1991; Hobbs and Parker, 1990; Morrell, 1989) . Clinical signs included abdominal distension and tachypnea. Cases were characterized by distension of the uterine horns with a transudative fluid. One case was associated with uterine torsion (Hobbs and Parker, 1990) . One case had resolved with diuretic therapy, only to return later (Bray et al., 1991) .

Most cases of liver lobe torsion in rabbits involve the caudate lobe (Bergdall and Dysko, 1994) , although one case report described torsion of the left hepatic lobe (Wilson et al., 1987) . Most reported cases have been incidental findings at necropsy. Incidental hepatic lobe torsions have also been identified in three adult New Zealand white rabbits that died from pasteurellosis (Weisbroth, 1975) . Three cases of hepatic torsion in pet rabbits were reported by Wenger in 2009 (Wenger et al., 2009) . All rabbits presented with an acute onset of lethargy, anorexia, abdominal pain, pale mucous membranes, and jaundice. One rabbit also had hematuria. Another report of caudate liver lobe torsion also described a rabbit that was jaundiced, anemic, and anorexic, with elevated alanine aminotransferase. Torsion of the caudate liver lobe was seen at necropsy (Fitzgerald and Fitzgerald, 1992) . In all reported clinical cases, rabbits were euthanized, or died during postoperative recovery.

Calcium carbonate and triple phosphate crystals are present in the urine of normal rabbits. These crystals contribute to the cloudy consistency of the urine (Williams, 1976) . A 9-year retrospective study of hematuria in 14 New Zealand White rabbits was conducted by Garibaldi (Garibaldi et al., 1987) . Physical examination, laboratory tests, radiography, and postmortem examination were utilized in most cases to verify the presence of hematuria and to determine its etiology. Uterine adenocarcinoma was diagnosed in two rabbits. Three rabbits had uterine polyps with hemorrhage. Renal infarction with hemorrhage was diagnosed in three rabbits. Urolithiasis with secondary urethral obstruction and hemorrhagic cystitis was identified as the cause of hematuria in four rabbits. Other causes of hematuria included chronic cystitis, disseminated intravascular coagulation, bladder polyps and pyelonephritis. Hematuria of undetermined origin was observed in one rabbit which emphasizes that hyperpigmented urine should be a rule out in all cases of suspected hematuria in rabbits (Garibaldi et al., 1987) . One case of urolithiasis with hydronephrosis in a New Zealand White rabbit was also reported (Labranche and Renegar, 1996) . This condition must be distinguished from hematuria caused by endometrial venous aneurysm in female rabbits (Bray et al., 1992) .

Herniation of the kidney along with perinephric fat has been reported (Suckow and Grigdesby, 1993) . The affected rabbit was clinically normal except for a subcutaneous mass that had passed through the body wall. The precise etiology is not known, although it was speculated that herniation might have occurred as the result of unreported trauma.

Occlusion of the nasolacrimal duct, presumably due to accumulation of fat droplets, has been described as a putative cause of epiphora in some rabbits (Marini et al., 1996) . Although the obstruction occurred at the dorsal flexure, it is not clear if this was due to congenital rather than acquired stenosis. In a retrospective study of 28 rabbits it was determined that the mean age of the rabbits presenting with ocular discharge from the nasolacrimal duct was 4.4 years. In 25 rabbits (89%), dacryocystitis was a unilateral finding. No underlying cause could be determined in 10 animals (35%). Dental malocclusion was observed in 14 rabbits (50%) and rhinitis in two animals (7%), with one animal showing both signs (4%). One rabbit (4%) presented with panophthalmitis. Most animals (96%) received topical antibiotic treatment. Regarding the clinical outcome, 12 animals (43%) showed complete recovery, eight rabbits (28%) were euthanized, three (11%) died due to unrelated causes, and three (11%) were lost to follow-up. Two rabbits (7%) continued to display signs of dacryocystitis (Florin et al., 2009) .

Development and genetic differences of complement activity in rabbits

Influence of Pasteurella multocida infection on the pharmacokinetic behavior of marbofloxacin after intravenous and intramuscular administrations in rabbits

Rabbit haemorrhagic disease (RHD) and rabbit haemorrhagic disease virus (RHDV): a review

Candidate vaccine antigens and genes in Pasteurella multocida

A survey of Clostridium spiroforme antimicrobial susceptibility in rabbit breeding

Vaccination of rabbits against coccidiosis using precocious lines of Eimeria magna and Eimeria media in Benin

Molecular characterization of Pasteurella multocida isolates from rabbits

Detection of cytokine mRNA in the lung during the spontaneous Pneumocystis carinii pneumonia of the young rabbit

Rabbit pasteurellosis: respiratory and renal pathology of control and immunized rabbits after challenge with Pasteurella multocida

Tyzzer's disease syndrome in laboratory rabbits

Trichoepithelioma in a rabbit

Transgenic rabbits expressing human lipoprotein lipase

Effects of Sarcoptes scabei var. canis (Acari: Sarcoptidae) on blood indexes of parasitized rabbits

Host-seeking behavior of Sarcoptes scabei

Histopathology in hosts parasitized by Sarcoptes scabei

Watanabe heritable hyperlipidemic rabbits. Familial hypercholesterolemia

Animal model: spontaneous adenocarcinoma in aged rabbits

Wild rabbits -a novel vector for Vero cytotoxigenic Escherichia coli (VTEC) O157

Clostridium spiroforme infection in rabbits

Dermatophytes in clinically healthy laboratory animals

In utero transmission of Encephalitozoon cuniculi strain type I in rabbits

Environmental enrichment for laboratory rodents and rabbits: requirements of rodents, rabbits, and research

Natural paratuberculosis infection in rabbits in Scotland

Rapid detection of Clostridium difficile in feces by real-time PCR

Metabolic, traumatic, mycotic, and miscellaneous diseases of rabbits

Fresh fruit and vegetables as vehicles for the transmission of human pathogens

Vitamin D toxicosis in commercially reared rabbits

Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with long-QT syndrome 1 both in vitro and in vivo

Intracranial teratoma in a domestic rabbit

O serogroups, biotypes, and eae genes in Escherichia coli strains isolated from diarrheic and healthy rabbits

Functional and morphological organization of the rabbit sinus node

Association of iota-like toxin and Clostridium spiroforme with both spontaneous and antibioticassociated diarrhea and colitis in rabbits

Pathogenomics of Pasteurella multocida

Viral diseases

Hydrometra in a New Zealand White rabbit

Endometrial venous aneurysms in three New Zealand White Rabbits

Efficacy of enrofloxacin in the treatment of respiratory pasteurellosis in rabbits

Studies based on a malignant tumor of the rabbit. I. The spontaneous tumor and associated abnormalities

Glucocorticoid metabolites in rabbit faeces -Influence of environmental enrichment and cage size

Compendium of normal blood values of laboratory animals with indication of variations

Development of ocular hypertension in congenitally buphthalmic rabbits

Epidemiology and risk factors for dermatophytoses in rabbit farms

Enzymatic activity of Microsporum canis and Trichophyton mentagrophytes from breeding rabbits with and without skin lesions

Molecular identification and phylogenesis of dermatophytes isolated from rabbit farms and rabbit farm workers

Perinatal development of glucogenic enzymes in rabbit liver

Evaluation of some coagulation parameters in hepatic coccidiosis experimentally induced with Eimeria stiedai in rabbits

Eimeria stiedae: experimental infection in rabbits and the effect of treatment with toltrazuril and ivermectin

Biotypes and O serogroups of Escherichia coli involved in intestinal infections of weaned rabbits: clues to diagnosis of pathogenic strains

Diarrhea due to Escherichia coli in the rabbit: a novel mechanism

The digestive system of the rabbit

Infectious nature of Clostridium spiroforme-mediated rabbit enterotoxaemia

Experimental and spontaneous clostridial enteropathies of laboratory and free living lagomorphs

In vitro susceptibility of rabbit strains of Clostridium spiroforme to antimicrobial agents

Structure of rrn operons in pathogenic non-cultivable treponemes: sequence but not genomic position of intergenic spacers correlates with classification of Treponema pallidum and Treponema paraluiscuniculi strains

Animal pneumocystosis: a model for man

In utero transmission of Pneumocystis carinii sp

Natural transmission of Pneumocystis carinii in nonimmunosuppressed animals: early contagiousness of experimentally infected rabbits (Oryctolagus cuniculus)

Obtaining a Pneumocystisfree rabbit breeding stock (Oryctolagus cuniculus)

Cryptosporidium sp. rabbit genotype, a newly identified human pathogen

Sporadic human cryptosporidiosis caused by Cryptosporidium cuniculus

Rabbit Feeding and Nutrition

Nutrition and nutritional diseases

Dermatophytoses in animals

Expression of recombinant human factor VIII in milk of several generations of transgenic rabbits

Quality of transgenic rabbit embryos with different EGFP gene constructs

Induction of pneumonia in rabbits by use of a purified protein toxin from Pasteurella multocida

Cottontail rabbit papillomavirus (CRPV) model system to test antiviral and immunotherapeutic strategies

Rabbit Genetics and Transgenic Models

A behavioral comparison of New Zealand White rabbits (Oryctolagus cuniculus) housed individually or in pairs in conventional laboratory cages

Relationship between food and water ingestion in the rabbit

Infection strategies of enteric pathogenic Escherichia coli

Animal and human pathogenic Escherichia coli strains share common genetic backgrounds

Facial alopecia in the rabbit associated with Cheyletiella parasitovorax

Cheyletiella dermatitis: a mite infestation of rabbit, cat, dog, and man

Intranasal vaccination of rabbits with Pasteurella multocida A:3 outer membranes that express ironregulated proteins

Natural pathogens of laboratory animals and their effects on research

Comparison of the 16S ribosomal DNA sequences from the intracellular agents of proliferative enteritis in a hamster, deer, and ostrich with the sequence of a porcine isolate of Lawsonia intracellularis

Diagnosis of proliferative enteritis in frozen and formalin-fixed, paraffin-embedded tissues from a hamster, horse, deer and ostrich using a Lawsonia intracellularis-specific multiplex PCR assay

Fluorescence-activated flow cytometry in the hematology clinical laboratory

Disorders of Carbohydrate Metabolism in Infancy

Altered immune responsiveness associated with Encephalitozoon cuniculi infection in rabbits

Bacillus piliformis' (Tyzzer) and Tyzzer's disease of the laboratory mouse. I. Propagation of the organism in embryonated eggs

Pneumocystis carinii pneumonia in four mammal species: histopathology and ultrastructure

Ultrastructure, immunoflourescence, western blot, and PCR analysis of eight isolates of Encephalitozoon (Septata) intestinalis established in culture from sputum and urine samples and duodenal aspirates of five patients with AIDS

Venereal spirochetosis of rabbits: description and diagnosis

Venereal spirochetosis of rabbits: epizootiology

Venereal spirochetosis of rabbits: eradication

Use of ivermectin for treatment of ear mite infestation in rabbits

An epizootic of Tyzzer's disease in rabbits

Experimental reproduction of neonatal diarrhea in young gnotobiotic hares simultaneously associated with Clostridium difficile and other Clostridium strains

Single primer polymerase chain reaction fingerprinting for Pasteurella multocida isolates from laboratory rabbits

Typing of Clostridium perfringens by in vitro amplification of toxin genes

Escherichia coli O157: H7 in environments of culture-positive cattle

Herpesvirus systematics

Respiratory diseases of rabbits

Pasteurella multocida and Bordetella bronchiseptica infections in rabbits

Pneumocystis oryctolagi sp. nov., an uncultured fungus causing pneumonia in rabbits at weaning: review of current knowledge, and description of a new taxon on genotypic, phylogenetic and phenotypic bases

Ingestion of rabbit erythrocytes containing 51Cr-labeled hemoglobin by Psoroptes spp. that originated on cattle, mountain sheep, or rabbits

Colonization of rabbits by Pasteurella multocida: serum IgG responses following intranasal challenge with serologically distinct isolates

Identification and characterization of three Encephalitozoon cuniculi strains

Treponema paraluis-cuniculi infection in a commercial rabbitry: epidemiology and serodiagnosis

Atrophic rhinitis in New Zealand White rabbits infected with Pasteurella multocida

Naturally acquired Pasteurella multocida infection in rabbits: immunological aspects

Naturally acquired Pasteurella multocida infection in rabbits: clinicopathological aspects

Hypervitaminosis A and reproductive disorders in rabbits

Ferrets, Rabbits, and Rodents

Production of recombinant human protein C in the milk of transgenic rabbits from the F3 generation

Development of PCR protocols for specific identification of Clostridium spiroforme and detection of sas and sbs genes

Vaccination against Eimeria magna coccidiosis using spray dispersion of precocious line oocysts in the nest box

A quantitative polymerase chain reaction assay for detection and quantification of Lawsonia intracellularis

Subclinical proliferative enteropathy in sentinel rabbits associated with Lawsonia intracellularis

Assignment of the agent of Tyzzer's disease to Clostridium piliforme comb. nov. on the basis of 16S rRNA sequence analysis

Control of oxyuriasis in rabbits by fenbendazole

Preliminary observations on enteritis associated with a coronavirus-like agent in rabbits

Evaluation of Pasteurella multocida isolated from rabbits by capsular typing, somatic serotyping, and restriction endonuclease analysis

Helminth infection in relation to population fluctuations in snowshoe hare

Silver staining of spirochaetes in single tissue sections

Effectiveness of a selamectin spot-on formulation in rabbits with sarcoptic mange

The effect of the fiber and protein level of the ration upon the cecotrophy of rabbits

Ribosomal RNA sequences of Clostridium piliforme isolated from rodent and rabbit: re-examining the phylogeny of the Tyzzer's disease agent and development of a diagnostic polymerase chain reaction assay

Teneur en acides amines des deux catégories de fèces du lapin: caecotrophes et fèces durés

Virulence genes and antimicrobial resistance profiles of Pasteurella multocida strains isolated from rabbits in Brazil

Hepatic lobe torsion in a New Zealand White rabbit

Identification of crystalline material in urine of rabbits

Renal nosematosis in young rabbits

Metabolic, traumatic, mycotic, and miscellaneous disease of rabbits

Clinical presentation, treatment, and outcome of dacryocystitis in rabbits: a retrospective study of 28 cases

Use of gonadotropic releasing hormone for ovulating the rabbit model

Influence of a genetically determined atropinesterase on atropine inhibition of the "smoke (dive) reflex" in rabbits

Intracellular Campylobacter-like organism from ferrets and hamsters with proliferative bowel disease is a Desulfovibrio sp

The Clinical Chemistry of Laboratory Animals

Taxonomy and genetics

Mandibular prognathism in the rabbit. Genetic studies

Strain differences in the prealbumin serum esterases of JAX rabbits

Buphthalmia in the rabbit. Pleiotropic effects of the (bu) gene and a possible explanation of mode of gene action

What is your diagnosis? Respiratory abscess

Polymerase chain reaction for diagnosis and species differentiation of microsporidia

Systemic inflammatory response indicators in rabbits (Oryctolagus cuniculus) experimentally infected with sporulated oocysts of Eimeria stiedai (Apicomplexa: Eimeriidae)

Pathology of protozoal and helminthic diseases

Toxigenic Pasteurella multocida in rabbits with naturally occurring atrophic rhinitis

Examination of the applicability of a commercial human rotavirus antigen detection kit for use in laboratory rabbits

Cyclical variations in the excretion of intestinal coccidial oocysts in the rabbit

Effect of heat and selected chemical disinfectants upon infectivity of spores of Bacillus piliformis (Tyzzer's disease)

Tyzzer's disease of rabbits: isolation and propagation of Bacillus piliformis (Tyzzer) in embryonated eggs

Development and application of TaqMan MGB probe fluorescence quantitative PCR method for rapid detection of Clostridium piliforme

The rabbit as a new reservoir host of enterohemorrhagic Escherichia coli

A naturally occurring rabbit model of enterohemorrhagic Escherichia coli-induced disease

Renal injury is a consistent finding in Dutch Belted rabbits experimentally infected with enterohemorrhagic Escherichia coli

Zoonotic enterohemorrhagic Escherichia coli: A One Health perspective

Hematuria in rabbits

Organ systems in adaptation: the temperature regulating system

Accuracy and coverage assessment of Oryctolagus cuniculus (rabbit) genes encoding immunoglobulins in the whole genome sequence assembly (OryCun2.0) and localization of the IGH locus to chromosome 20

Tpr homologs in Treponema paraluiscuniculi Cuniculi A strain

Inherited neuroaxonal dystrophy in C6 deficient rabbits

Fibres in rabbit feeding for digestive troubles prevention: respective role of low-digested and digestible fibre

Feeding behaviour of rabbits

Selected drug dosages and clinical reference data

Medical and surgical management of gastric obstruction from a hairball in the rabbit

The complete mitochondrial DNA sequence of the rabbit

Infection with and antibody response to Pasteurella multocida and Bordetella bronchiseptica in immature rabbits

The pathology of experimental respiratory infection with Pasteurella multocida and Bordetella bronchiseptica in rabbits

Quantitation of rabbit cytokine mRNA by real-time RT-PCR

Detection of toxigenic Clostridium difficile in diarrheal stools by rapid real-time polymerase chain reaction

The effect of host's age on the pathology of Eimeria stiedae infection in rabbits

A spontaneous melanoma in the hamster with a propensity for amelanotic alteration and sarcomatous transformation during transplantation

Diseases of the rabbit

Multiple primary tumors in the rabbit

Paratuberculosis in wild rabbits (Oryctolagus cuniculus)

Inventory of the behaviour of New Zealand White rabbits in laboratory cages

Identification of genes transcribed by Pasteurella multocida in rabbit livers through the selective capture of transcribed sequences

Detection and characterization of Cryptosporidium cuniculus by real-time PCR

1970. Rabbits. In: Reproduction and Breeding Techniques for Laboratory Animals. Lea & Febiger

The effects of continuous sulfaquinoxaline feeding on rabbit mortality

Spontaneous papillomatosis in domestic rabbits

Antibacterial efficacy and pharmacokinetic studies of ciprofloxacin on Pasteurella multocida infected rabbits

Recessive buphthalmos in the rabbit

The effect of environmental enrichment on the behaviour of caged rabbits

Microbial induction of B and T cell areas in rabbit appendix

The Biology and Medicine of Rabbits and Rodents

Pathogenesis of Herpesvirus sylvilagus infection in cottontail rabbits

Normal biochemical and hematological values in New Zealand White rabbits

Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome

Transgenic rabbit production with simian immunodeficiency virus-derived lentiviral vector

Syphilis: using modern approaches to understand an old disease

Uterine torsion associated with either hydrometra or endometritis in two rabbits

Atrioventricular conduction in mammalian hearts

Arthropod and helminth parasites

Isolation of Clostridium spiroforme from rabbits

Proliferative enteropathy involving Lawsonia intracellularis infection in rabbits (Oryctlagus cuniculus)

Coecotrophy in rabbits-A circadian function

The route of migration of Eimeria stiedae (Lindemann, 1865) sporozoites between the duodenum and bile duct of the rabbit

The treatment of hepatic coccidiosis in rabbits

Malignant melanomas in two rabbits

Proliferative enteropathy of rabbits: the intracellular Campylobacter-like organism is closely related to Lawsonia intracellularis

Real-time multiplex polymerase chain reaction assay for rapid detection of Clostridium difficile toxin-encoding strains

Mandibular prognathism in the rabbit: discrimination between single-locus and multifactorial models of inheritance

Natural mode of acquisition for de novo infection with Pneumocystis carinii

Response of adult New Zealand White rabbits to enrichment objects and paired housing

Hereditary compulsive self-mutilating behaviour in laboratory rabbits

Spontaneous cryptosporidiosis in an adult female rabbit

Liver coccidiosis prevented by sulfasuxidine

Pasteurella associated rhinitis of rabbits: efficacy of penicillin therapy

Atherosclerotic research

A new model of sheep Ig diversification: shifting the emphasis toward combinatorial mechanisms and away from hypermutation

The rabbit: a diurnal or nocturnal animal?

Characterization of a novel alphaherpesvirus associated with fatal infections of domestic rabbits

An outbreak of fatal herpesvirus infection in domestic rabbits in Alaska

Proteomic analyses of transgenic LQT1 and LQT2 rabbit hearts elucidate an increase in expression and activity of energy producing enzymes

Ovarian abscesses and pyometra in a domestic rabbit

An epizootic of Shope fibromatosis in a commercial rabbitry

Enhanced detection of intracellular organism of swine proliferative enteritis, ileal symbiont intracellularis, in feces by polymerase chain reaction

Eimeria stiedae in rabbits: the demonstration of responses to chemotherapy

Pure culture of the pathogenic agent of Tyzzer's disease of mice

Molecular approaches in the diagnosis of dermatophytosis

Pathogenic Escherichia coli

Beat-to-beat regulation of heart rate by afferent stimulation of the aortic nerve

Implantable stimulating electrode for baroreceptor afferent nerves in rabbits

Spontaneous renal carcinoma in a New Zealand White rabbit

An outbreak of massive mortality among farm rabbits associated with Cryptosporidium infection

Growth of Tyzzer's organism in primary monolayer cultures of adult mouse hepatocytes

The comparative pathology of Clostridium difficile-associated disease

Superovulatory response of pre-and post-pubertal rabbits to commercially available gonadotropins

Viral infections of rabbits

A transplantable rabbit carcinoma originating in a virus-induced papilloma and containing the virus in masked or altered form

Cloning and sequence analysis of another Shiga-like toxin IIe variant gene (slt-IIera) from an Escherichia coli R107 strain isolated from rabbit

Ependymoma in a rabbit

Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia

Peripheral thermal sensitivity in the rabbit

Ultrastructural studies of primary congenital glaucoma in rabbits

Spontaneous Nosema cuniculi infection in laboratory rabbits

Genetic deficiency of the alpha-gamma-subunit of the eighth complement component in the rabbit

Hereditary C3 hypocomplementemia in the rabbit

Hereditary C8α-γ deficiency associated with dwarfism in the rabbit

Environmental factors, clinical signs, therapy and zoonotic risk of rabbits with dermatophytosis

Biology and diseases of rabbits

Localization of human coagulation factor VIII (hFVIII) in transgenic rabbit by FISH-TSA: identification of transgene copy number and transmission to the next generation

Encephalitozoonosis in rabbits

New mutant rabbit strain with hypercholesterolemia and atherosclerotic lesions produced by serial inbreeding

Use of selamectin for the treatment of psoroptic and sarcoptic mite infestation in rabbits

Urinary calculus and hydronephrosis in a New Zealand White rabbit

Preliminary report on the observation of a coronavirus in the intestine of the laboratory rabbit

Hereditary hyperlipidemia in the rabbit due to overproduction of lipoproteins, I. Biochemical studies

Proliferative enteropathy

Experimental and naturally-occuring gastric foreign bodies in laboratory rabbits

Vitamins in rabbit nutrition: literature review and recommendations

Farmed rabbits and ducks as vectors for VTEC O157:H7

Cheyletiella dermatitis: a report of fourteen cases

Abnormal platelet response to thromboplastin infusion in rabbits deficient in the sixth component of complement

Value of histopathology, immunohistochemistry, and real-time polymerase chain reaction in the confirmatory diagnosis of Encephalitozoon cuniculi infection in rabbits

Fecal occult blood manifestation of intestinal Eimeria spp. infection in rabbit

Production of transgenic rabbit embryos through intracytoplasmic sperm injection

A spontaneous skin basal cell tumor in a black French minilop rabbit

Peritoneal mesothelioma in the rabbit

Tyzzer's disease

Catalytic enzyme activity concentration in plasma of man, sheep, dog, cat, rabbit, guinea pig, rat, and mouse

Seasonal and sexual influence on rabbit atropinesterase

Prevalence of Lawsonia intracellularis, Salmonella spp. and Eimeria spp. in healthy and diarrheic pet rabbits

Inherited diseases and variations

Expression of human growth hormone in the milk of transgenic rabbits with transgene mapped to the telomere region of chromosome 7q

Utilization of cholestyramine resin as a preventative treatment for antibiotic (clindamycin) induced enterotoxemia in the rabbit

Prolactin-secreting pituitary adenomas with mammary dysplasia in New Zealand White rabbits

Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits

Complete genome sequence of Pasteurella multocida HN06, a toxigenic strain of serogroup D

Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms

Dermatophytes isolated from laboratory animals

Group housing: meeting the physical and social needs of the laboratory rabbit

An enzymelinked immunosorbent assay to detect serum IgG to Pasteurella multocida in naturally and experimentally infected rabbits

Comparison of 61 sequenced Escherichia coli genomes

Is there a difference between hare syphilis and rabbit syphilis? Cross infection experiments between rabbits and hares

Immunoprophylaxis of dermatophytosis in animals

The effect of sulfaquinoxaline on the course of Eimeria stiedae infection in the domestic rabbit

Estimating relative pollution of the environment with oocysts of Eimeria stiedae

Immunology of Lagomorphs

B cell and antibody repertoire development in rabbits: the requirement of gut-associated lymphoid tissues

Rhythmic contractile activity of the in vivo rabbit aorta

Serology of Pasteurella multocida in laboratory rabbits: a review

Microbiologic, radiographic, and anatomic study of the nasolacrimal duct apparatus in the rabbit (Oryctolagus cuniculus)

Worsening of diet-induced atherosclerosis in a new model of transgenic rabbit expressing the human plasma phospholipid transfer protein

Two Encephalitozoon cuniculi strains of human origin are infectious to rabbits

LsaA, an antigen involved in cell attachment and invasion, is expressed by Lawsonia intracellularis during infection in vitro and in vivo

Vitamins in Animal Nutrition

Clinical and pharmacological properties of ivermectin in rabbits and guinea pigs

Myeloid leukemia in the rabbit

Treatment of rabbit chyletiellosis with selamectin or ivermectin: a retrospective case study

Pathogenesis of Shiga-toxin producing Escherichia coli

Pathogenesis of dermatophytosis and Tinea versicolor

Rabbit hemorrhagic disease: a review with special reference to its epizootiology

Clinical Biochemical and Hematological Reference Values in Normal Experimental Animals and Normal Humans

Introduction: one health perspective

Intraepithelial vibrio associated with acute typhlitis of young rabbits

Infection of different strains of mice with Lawsonia intracellularis derived from rabbit or porcine proliferative enteropathy

Ectoparasites of the wild rabbit, Oryctolagus cuniculus (L.) in Australia

Rabbitpox: a model of airborne transmission of smallpox

Colobomatous microphthalmos in a New Zealand White rabbit, arising from a colony with suspected vitamin E deficiency

Development of a high-sensitivity nested PCR assay for the detection of Clostridium piliforme in clinical samples

Acquired resistance to reinfection of rabbits with Eimeria magna

The rabbit differs from other mammalian species in the tissue distribution of alkaline phosphatase isoenzymes

Immunological responses to vaccination following experimental Lawsonia intracellularis virulent challenge in pigs

Clinical efficacy of botanical extracts from Eupatorium adenophorum against the Sarcoptes scabiei (Sarcoptidae: Sarcoptes) in rabbits

Walker's Mammals of the World

Antibiograms of pathogenic bacteria isolated from laboratory rabbits in Ibadan

Eimeria species of the domestic rabbit (Oryctolagus cuniculus)

Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation

Life cycle of Eimeria stiedae

The reproduction of Eimeria flavescens and Eimeria intestinalis in suckling rabbits

The rabbit coccidium Eimeria piriformis: selection of a precocious line and life-cycle study

Protozoal diseases

Protozoal diseases

Rapid detection of Clostridium difficile toxins from stool samples using real-time multiplex PCR

Efficacy of an injectable formulation of eprinomectin against Psoroptes cuniculi, the ear mange mite in rabbits

Identification of the cellular receptor of Clostridium spiroforme toxin

Acaricidal activity of eugenol based compounds against scabies mites

Plasma cell myeloma in the brain of a rabbit

An outbreak of encephalomyelitis in broiler rabbits caused by Nosema cuniculi

Diagnostic performance of different fecal Lawsonia intracellularis-specific polymerase chain reaction assays as diagnostic tests for proliferative enteropathy in pigs: a review

Significance of Clostridium spiroforme in the enteritis-complex of commercial rabbits

Biotype, serotype, and pathogenicity of attaching and effacing enteropathogenic Escherichia coli strains isolated from diarrheic commercial rabbits

Three ectoparasites of veterinary interest communicable to man

Coccidia and Coccidiosis

Parenteral infection experiments with Eimeria stiedae

Transgenic rabbit models for studying human cardiovascular diseases

Meningitis and subgaleal, subdural, epidural empyema due to Pasteurella multocida

Detection of Clostridium difficile toxins from the small intestine and cecum of rabbits with naturally acquired enterotoxemia

Molecular bases of genetic diversity and evolution of the immunoglobulin heavy chain variable region (IGHV) gene locus in leporids

Rearing germfree cesarean-born rats, mice, and rabbits through weaning

Spontaneous malignant hemangiosarcomas in two rabbits

The behaviour of group penned and individually caged laboratory rabbits

Genetic characterization of antibiotic resistance in enteropathogenic Escherichia coli carrying extendedspectrum beta-lactamases recovered from diarrhoeic rabbits

Environmental enrichment of New Zealand White rabbits living in laboratory cages

Identification of eae sequences in enteropathogenic Escherichia coli strains from rabbits

A sebaceous gland carcinoma in a rabbit

Tyzzer's disease in rabbits in Britain

Pneumocystosis in humans or in corticosteroid-untreated animal models: interactions between pulmonary surfactant changes and Pneumocystis carinii in vivo or in vitro growth

Wild rabbits-a novel vector for verocytotoxigenic Escherichia coli O157

Evaluation of available diagnostic methods for Clostridium piliforme in laboratory rabbits (Oryctolagus cuniculus)

Further investigation of exposure to Lawsonia intracellularis in wild and feral animals captured on horse properties with equine proliferative enteropathy

Efficacy of an avirulent live vaccine against Lawsonia intracellularis in the prevention of proliferative enteropathy in experimentally infected weanling foals

Transmission of Lawsonia intracellularis to weanling foals using feces from experimentally infected rabbits

Outbreak of sarcoptic mange and malasseziasis in rabbits (Oryctolagus cuniculus)

Characterization of a fibroma virus isolated from naturally-occurring skin tumors in domestic rabbits

The pangenome structure of Escherichia coli: comparative genomic analysis of E. coli commensal and pathogenic isolates

Sudden death syndrome in adult cows associated with Clostridium perfringens type E

Cryptosporidium cuniculus in the rabbit (Oryctolagus cuniculus)

Clostridium difficile colitis in a rabbit following antibiotic therapy for pasteurellosis

Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans

Comparative metabolism of tritiated water by mammals

Cytotoxicity of Bacillus piliformis

Nutritional muscular dystrophy and neonatal mortality in a rabbit breeding colony

Laboratory diagnosis of vitamin E deficiency in rabbits fed a faulty commercial ration

Conventional methods for the diagnosis of dermatophytosis

Hydrocephalus and cleft palate in an inbred rabbit colony

Re-description of Cryptosporidium cuniculus Inman and Takeuchi, 1979 (Apicomplexa: Cryptosporidiidae): morphology, biology and phylogeny

Production of transgenic rabbits

A study of the life cycle of Eimeria stiedae (Lindemann, 1865) and the immunological response of the host

Immunocytochemistry of Psoroptes cuniculi stained by sera from naive and infested rabbits: preliminary results

Deficiency of the sixth component of complement in rabbits with an inherited complement defect

The life cycle of four intestinal coccidia of the domestic rabbit

Genome Sequence of Lawsonia intracellularis Strain N343, Isolated from a Sow with Hemorrhagic Proliferative Enteropathy

A cottontail rabbit papillomavirus strain (CRPVb) with striking divergent E6 and E7 oncoproteins: an insight in the evolution of papillomaviruses

Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy

Exploring transplacental transmission of Pneumocystis oryctolagi in first-time pregnant and multiparous rabbit does

Health and body condition of lactating females on rabbit farms

Atropinesterase, a genetically determined enzyme in the rabbit

Wild rabbits (Oryctolagus cuniculus) as potential carriers of verocytotoxin-producing Escherichia coli

Proliferative enterocolitis associated with dual infection with enteropathogenic Escherichia coli and Lawsonia intracellularis in rabbits

Complement C6 deficiency protects against diet-induced atherosclerosis in rabbits

Quantitative RT-PCR profiling of the rabbit immune response: assessment of acute Shigella flexneri infection

Enterocecocolitis associated with intraepithelial Campylobacter-like bacteria in rabbits (Oryctolagus cuniculus)

Rotavirus-associated diarrhea in a commercial rabbitry

Parasites of Rabbits

In vitro inhibition of Clostridium difficile and Clostridium perfringens by commercial probiotic strains

Some factors in the in vitro infectivity and replication of Encephalitozoon cuniculi

The oxidative status and inflammatory level of the peripheral blood of rabbits infested with Psoroptes cuniculi

Glycogen reserves and their changes at birth

Cryptosporidium infection in juvenile pet rabbits

Aortic endograft infection due to Pasteurella multocida following a rabbit bite

Analysis of the expression of platelet antigens CD9 and CD41/61 in transgenic rabbits with the integrated human blood clotting factor VIII gene construct

Psoroptes cuniculi induced oxidative imbalance in rabbits and its alleviation by using vitamins A, D3, E, and H as adjunctive remedial

Complete genome sequence of Treponema paraluiscuniculi, strain Cuniculi A: the loss of infectivity to humans is associated with genome decay

Genetic diversity in Treponema pallidum: implications for pathogenesis, evolution and molecular diagnostics of syphilis and yaws

Venereal spirochetosis of rabbits (rabbit syphilis) due to Treponema cuniculi: a clinical, serological, and histopathological study

Coccidiosis of the live rabbit II, Experimental study on the mode of infection of the liver by sporozoites of Eimeria stiedae

Lawsonia intracellularis: getting inside the pathogenesis of proliferative enteropathy

Gamma interferon influences intestinal epithelial hyperplasia caused by Lawsonia intracellularis infection in mice

Bacillus piliformis infection (Tyzzer's disease) in a patient infected with HIV-1: confirmation with 16S ribosomal RNA sequence analysis

Production of two vaccinating recombinant rotavirus proteins in the milk of transgenic rabbits

Clostridial enteric diseases of domestic animals

The young rabbit: a nonimmunosuppressed model for Pneumocystis carinii pneumonia

Helminth, Arthropods, and Protozoa of Domestic Animals

Efficacy of ivermectin against nematodes infecting field populations of snowshoe hares (Lepus americanus) in Yukon

Novel bivalent vectored vaccine for control of myxomatosis and rabbit haemorrhagic disease

The current status and future directions of myxoma virus, a master in immune evasion

Phenotypic and genetic characterization of Pasteurella multocida and related isolates from rabbits in Switzerland

Altered myofilament stoichiometry in response to heart failure in a cardioprotective alpha-myosin heavy chain transgenic rabbit model

Glomerular blood flow

Biochemical modulation of 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits

Polyclonal antibody production

Rabbit cardiovascular responses during PEEP before and after vagotomy

Atropinesterase and cocainesterase of rabbit serum: localization of the enzyme activity in isozymes

Production of actin-specific ADP-ribosyltransferase (binary toxin) by strains of Clostridium difficile

The Laboratory Rabbit

Spontaneous lateral abdominal (lumbar) hernia in a New Zealand White rabbit

Immunization of rabbits against Pasteurella multocida using a commercial swine vaccine

Heat-labile toxinproducing isolates of Pasteurella multocida from rabbits

Protective immunity to Pasteurella multocida heat-labile toxin by intranasal immunization in rabbits

Derivation of Pasteurella multocida-free rabbit litters by enrofloxacin treatment

Immunization of rabbits against a bacterial pathogen with an alginate microparticle vaccine

Field trial of a Pasteurella multocida extract vaccine in rabbits

A comparative overview of immunoglobulin genes and the generation of their diversity in tetrapods

Intracutaneous vaccination of rabbits with the cottontail rabbit papillomavirus (CRPV) L1 gene protects against virus challenge

Prevention and treatment of Encephalitozoon cuniculi infection in rabbits with fenbendazole

Enteropathogenic Escherichia coli prevalence in laboratory rabbits

Enzootic enteropathogenic Escherichia coli infection in laboratory rabbits

Rearing of germfree rabbits and establishment of an SPF rabbit colony

Pinworm infection in laboratory rodents: a review

Establishment and characterization of CAG/ EGFP transgenic rabbit line

Pneumocystis carinii infection in young non-immunosuppressed rabbits. Kinetics of infection and of the primary specific immune response

Shiga toxin-associated hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: distinct mechanisms of pathogenesis

Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome

A clinical and pathological study of inherited glaucoma in New Zealand White rabbits

The effect of combined rotavirus and Escherichia coli infection in rabbits

Rabbit neoplasia

Novel transgenic rabbit model sheds light on the puzzling role of matrix metalloproteinase-12 in atherosclerosis

Studies on the Renal Circulation

Comparative morphology of the cardiac conduction tissue in animals

Water intake in domestic rabbits (Oryctolagus cuniculus) from open dishes and nipple drinkers under different water and feeding regimes

Intermittent medication of sulfadimethoxine and sulfamonomethoxine for the treatment of coccidiosis in domestic rabbits

Biology of the treponematoses based on studies carried out at the International Treponematosis Laboratory Center of the Johns Hopkins University under the auspices of the World Health Organization

Histiocytic enteritis of rabbits

Evidence of host adaptation in Lawsonia intracellularis infections

Large-scale management systems and parasite populations: coccidia in rabbits

Clinical Veterinary Advisor Birds and Exotic Pets

Pathogenesis of dermatophytosis

Thymoma in a rabbit with hypercalcemia and periodic exophthalmus

Detection of DNA sequences identical to Pneumocystis carinii in samples of ambient air

DNA sequences identical to Pneumocystis carinii f. sp. carinii and Pneumocystis carinii f. sp. hominis in samples of air spora

Mammalian microsporidiosis

Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit)

Breeding of a rabbit strain of hyperlipidemia and characteristic of this strain (author's transl)

The effect of selective breeding on the development of coronary atherosclerosis in WHHL rabbits. An animal model for familial hypercholesterolemia

Enzyme-linked immunosorbent assay to detect Lawsonia intracellularis in rabbits with proliferative enteropathy

Detection of Lawsonia intracellularis using immunomagnetic beads and ATP bioluminescence

Cultivation and characterization of Lawsonia intracellularis isolated from rabbit and pig

Efficacy of simultaneous vaccination with Enterisol(R) Ileitis and Ingelvac(R) CircoFLEXTM in a Swiss breeding farm

Neoplastic diseases

Torsion of the caudate lobe of the liver in the domestic rabbit (Oryctolagus)

Neoplastic diseases

Microsporidiosis: molecular and diagnostic aspects

Liver lobe torsion in three adult rabbits

Ultramicroelectric recording from cardiac pacemaker

The effects of group housing on the research use of the laboratory rabbit

Pasteurella multocida: diseases and pathogenesis

Practical Guide to Laboratory Animals

Ophthalmology of Exotic Pets

The effects of ethylene dibromide on semen quality and fertility in the rabbit: evaluation of a model for human seminal characteristics

DNA polymorphisms amplified by arbitrary primers are useful as genetic markers

Liver lobe torsion in a rabbit

Tularemia, plague, yersiniosis, and Tyzzer's disease in wild rodents and lagomorphs in Canada: a review

Reference range data base for serum chemistry and hematology values in laboratory animals

Infectious motor paralysis in young rabbits

Comparative efficacy of injection routes and doses of ivermectin against Psoroptes in rabbits

Pathology of spontaneous malignant fibrous histiocytoma in a Japanese White rabbit (Oryctolagus cuniculus)

Simultaneous identification of three highly pathogenic Eimeria species in rabbits using a multiplex PCR diagnostic assay based on ITS1-5.8S rRNA-ITS2 fragments

The Oct4 promoter-EGFP transgenic rabbit: a new model for monitoring the pluripotency of rabbit stem cells

Flow-volume curves of excised right and left rabbit lungs

Biochemical parameters of normal rabbit serum

A genomic update on clostridial phylogeny: gram-negative spore formers and other misplaced clostridia

A blood coagulation abnormality in rabbits deficient in the sixth component of complement (C6) and its correction by purified C6

Origin of complex behaviour of spatially discordant alternans in a transgenic rabbit model of type 2 long QT syndrome