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Comparative Medicine
Volume 57, Number 2, April 2007
OVERVIEWS
Rowland. Food or Fluid Restriction in Common Laboratory Ani...
ANSWERS:
1) 10 and dark cycle
2) 11% activity level did not decrease until 96 hours
3) F
4) F
5) F
Stevens and Balahura. A...
ANSWERS:
1. a
2. b
3. False; albumin is present in the plasma of some fish but absent in others.
4. b.
5. c.
ORIGINAL RESE...
ANSWERS:
1. True
2. c
Hariri et al. Ex Vivo Optical Coherence Tomography and Laser-induced
Fluorescence Spectroscopy Imagi...
smaller-diameter endoscopes for endoscopic esophageal imaging and laparoscopic
small intestine and upper colon imaging.
QU...
4. T/F Leukotrienes are elevated in broncho-alveolar lavage fluid from humans with
persistent pulmonary hypertension, obst...
1. BUN can be used to assess Cy carrier status in what sex and age of SPRD-
Pkdr1/Rrrc rats?
2. At what age were cysts vis...
A nephrectomy was performed on sixty-four, 250-300g Wistar rats. Fifteen days later,
the anterior mesenteric artery (provi...
or behavioral effects. In their natural habitat, approximately half of the owl monkeys are
infected with this nematode. Th...
SUMMARY: Spontaneous exocrine pancreas hypoplasia has not been previously
reported in mice. This article is a case study o...
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  1. 1. Comparative Medicine Volume 57, Number 2, April 2007 OVERVIEWS Rowland. Food or Fluid Restriction in Common Laboratory Animals: Balancing Welfare Considerations with Scientific Inquiry, pp. 149-160 Species: Mice and Rats Task: 3; Provide Research Support, Information, and Services SUMMARY: Deprivation or restricted access to food and/or water is essential to certain types physiological or behavior research. Deprivation studies withhold food or water for a set period or time, the animals are then tested, and returned to free excess. Restriction studies withhold only a portion of the daily food or water intake, usually for a prolonged period. In the normal lab setting, rodents usually have continual access to food and water for the convenience of the husbandry staff. Rodents typically become "grazers", in that they will eat and drink small amounts throughout the daily period, mostly during the dark cycle. In nature, this is usually not the case, and the animal needs to travel to food and water source, so does not consume as many meals per day. This free, continual, access to food often leads to obesity and decreased life longevity. When water is removed from rats and mice, they will decrease food intake. This results increased retention of water by less intake of electrolytes and decreased water loss through defecation. Rats will loss 4% of body weight in the 1st 24 hours and 11% by 72 hours. Activity levels did not decrease until 96 hours. Withholding water for 21 hours led to increased motivation in a water reward task vs. withholding for 14 hours. Mice will lose 7-9.5% body weight by 24 hours because of their smaller body size and increased water consumption (25% of body weight/day vs. 10% for rats). The author summarized by stating both mice and rats can normally have water withheld for 24 hours without overt signs of distress or abnormalities. Animals on long term restrictions should be weighed regularly. When food is withheld from rats, they lose 7% body weight by 24 hours and 17% by 72 hours. Activity levels actually increase. Rodents will quickly start to use body fat reserves for energy metabolism. Rats fed at 75% and 48% of ad libitum consumption had lower weight gain with much lower body fat content and higher survivability compared to rats fed ad libitum. Housing temperature needs to be considered, as low environmental temperature will lead to increased physiological metabolism. QUESTIONS: 1) Rats and mice fed ad libitum will typically consume (2, 4, 6, 8, or 10) meals per day, mostly during the __________ cycle. 2) Rats deprived of water for 72 hours lost (8, 11, 14, 17%) of body weight and activity level was (decreased, increased, same). 3) T/F Withholding water for 21 hours vs. 14 hours did not increase water reward motivation. 4) T/F Since mice consume more water as a percent of body weight, they can withstand longer periods of water deprivation. 5) T/F Rats fed at 48% of ad libitum do not survive as long as rats fed ad libitum.
  2. 2. ANSWERS: 1) 10 and dark cycle 2) 11% activity level did not decrease until 96 hours 3) F 4) F 5) F Stevens and Balahura. Aspects of Morphine Chemistry Important to Persons Working with Cold-blooded Animals, Especially Fish, pp. 161-166 SUMMARY: The relative amounts of the different forms of morphine and many other pharmacologic agents depend on temperature and pH. Some forms are more efficacious because they are uncharged and can penetrate lipid membranes more easily than the charged forms. Persons who administer pharmacologic agents to ectotherms (that is, cold-blooded animals) should consider the effects of temperature on the relative amounts of the different forms of drugs. For example, the fraction of morphine present in the uncharged form is twice as high in a fish or frog at 5 C as in a mammal at 37 C. Moreover, because the pH of blood, plasma, and tissues of ectotherms is higher when they are held at lower temperatures, the combined effect of temperature and pH on the speciation of pharmacologic agents also should be considered. In addition, the total solubility of morphine and other pharmacologic agents depends on temperature and pH. The purpose of this overview is to describe how temperature and Ph influence the solubility and speciation of morphine. QUESTIONS: 1. The common ion effect is? a. The reduction in solubility of a sparingly soluble salt by the addition of a soluble salt that has an ion in common with it. b. An increase in solubility of a soluble salt by the addition of a soluble salt that has an ion in common with it. c. An increase in solubility of a soluble salt by the addition of a soluble salt that does not have an ion in common with it. 2. When administered to mammals about _______ of morphine is bound to plasma proteins. a. One-half b. One-third c. Two-thirds 3. True or false: Albumin is present in the plasma of all fish. 4. Total solubility of morphine __________ with ___ __________ in temperature. a. Increases, a decrease b. Increases, an increase c. Decreases, an increase d. Decreases, a decrease 5. Total solubility of morphine _________ with _______________ in pH. a. Increases, a decrease b. Increases, an increase c. Decreases, an increase d. Decreases, a decrease
  3. 3. ANSWERS: 1. a 2. b 3. False; albumin is present in the plasma of some fish but absent in others. 4. b. 5. c. ORIGINAL RESEARCH Mouse Models Mast and Griff. The Effects of Analgesic Supplements on Neural Activity in the Main Olfactory Bulb of the Mouse, pp. 167-174 Task: Task 2 - Prevent, Alleviate, and Minimize Pain and Distress Species: Primary - mouse SUMMARY: Opioid analgesics such as buprenorphine may alter neuronal activity and therefore may not be the ideal antinociceptive for use during in vivo neurophysiologic recordings. NSAIDs such as ketoprofen may provide analgesia and reduce the amount of anesthetic needed during in vivo neurophysiologic recordings, but may also alter neuronal activity. This group therefore investigated the effects of ketoprofen on main olfactory bulb (MOB) neuronal spontaneous activity in the mouse under chloral hydrate anesthesia. ICR and B6 mice were anesthetized with chloral hydrate (400 mg/kg IP plus 30-70 mg/kg IP supplementation as needed). Mice were instrumented to record spontaneous MOB activity. Mice additionally received buprenorphine (0.02-0.2 mg/kg) or ketoprofen (100-200 mg/kg) after baseline MOB activity was established. Buprenorphine decreased the rate of MOB activity in a dose-dependent manner but did not affect temporal patterning. In contrast, ketoprofen did not affect spontaneous rate or temporal patterning of MOB activity. Additionally, ketoprofen decreased the amount of chloral hydrate needed to maintain an adequate anesthetic plane when ketoprofen was administered at the beginning of an experiment. In conclusion, ketoprofen deepens the anesthetic plane in chloral hydrate anesthetized mice but did not significantly alter MOB spontaneous activity. The authors recommend administering ketoprofen at 100 mg/kg in conjunction with chloral hydrate when investigating neurophysiology of MOB neurons. QUESTIONS: 1. True or false: NSAIDs such as ketoprofen cross the blood-brain-barrier and therefore may have some analgesic properties through central nervous system effects. 2. Which analgesic was shown to deepen the anesthetic plane of mice under chloral hydrate anesthesia but did not significantly inhibit spontaneous activity of the main olfactory bulb neurons? a. Buprenorphine b. Butorphanol c. Ketoprofen d. Ibuprofen
  4. 4. ANSWERS: 1. True 2. c Hariri et al. Ex Vivo Optical Coherence Tomography and Laser-induced Fluorescence Spectroscopy Imaging of Murine Gastrointestinal Tract, pp. 175-185 Species: Mice Task: 9; Collaborate on the Selection and Development of Animal Models SUMMARY: Optical coherence tomography (OCT) is a nondestructive, high resolution imaging modality that has been investigated for a vast array of applications, including imaging the anterior chamber of the eye and intracoronary stenting. OCT provides cross-sectional images with short penetration depths (1 to 2 mm) and can operate with either a water or air interface between the tissue and imaging probe. Laser-induced fluorescence (LIF) spectroscopy measures the autofluorescence of biochemical components such as NADH, collagen, and porphyrin excited by ultraviolet to green wavelengths of light, providing biochemical information about a specimen. The motivation for the use of OCT and LIF lies in their noninvasive nature. Mouse models of human pathologies can be used to enhance knowledge of pathologic processes and test therapeutic and chemopreventative compounds. Mouse models of colorectal cancer now available include the C57BL/6J-ApcMin strain, which exhibits an autosomally inherited predisposition to multiple intestinal neoplasia. Mouse models of inflammatory bowel disease (IBD) also exist, such as the interleukin 2 (B6.129P2- Il2tm1Hor, IL2)-deficient mouse. Mice deficient for IL2 have a 50% mortality rate by 9 wk of age. The remaining mice develop IBD that is clinically and histologically similar to ulcerative colitis and reportedly die within 10 to 25 wk under conventional housing conditions. Authors evaluated 30 normal mice (A/J and 10- and 21-wk-old and retired breeder C57BL/6J) and 10 mice each of 2 strains modeling colon cancer and IBD (ApcMin and IL2-deficient mice, respectively). Histology was used to classify tissue regions as normal, Peyer patch, dysplasia, adenoma, or IBD. Features in corresponding OCT images were analyzed. Spectra from each category were averaged and compared via Student t tests. Based on the preliminary data, authors suggest that together, OCT and LIF can potentially be used to distinguish the categories of normal, Peyer patch, adenoma or dysplasia, and IBD. Therefore combined OCT-LIF may be another tool for evaluating the GI tract of mouse models and may provide the capability to monitor the effects of drug treatment and experimental therapies in mouse models of human disease. Further studies with more diseased animals are needed to fully assess the significance of our findings. Both OCT and fluorescence spectroscopy have the capability to be used for in vivo imaging applications of the GI tract, as they are both readily adaptable to small- diameter endoscopic packaging with relative ease. Future work includes developing
  5. 5. smaller-diameter endoscopes for endoscopic esophageal imaging and laparoscopic small intestine and upper colon imaging. QUESTIONS: 1) Name a mouse model of inflammatory bowel disease (IBD)? 2) What is Optical coherence tomography (OCT)? 3) T/F Mice deficient for IL2 have a 50% mortality rate by 9 wk of age 4) T/F IL/2 deficient mice develop IBD that is clinically and histologically similar to Crohn's disease and reportedly die within 10 to 25 wk under conventional housing conditions. ANSWERS: 1) Interleukin 2 (B6.129P2-Il2tm1Hor, IL2)-deficient mouse 2) Optical coherence tomography (OCT) is a nondestructive, high resolution imaging modality that has been investigated for a vast array of applications, including imaging the anterior chamber of the eye and intracoronary stenting 3) T 4) F (histologically similar to ulcerative colitis) Rat Models Funk et al. Effects of Leukotriene Inhibition on Pulmonary Morphology in Rat Pup Lungs Exposed to Hyperoxia, pp. 186-192 Primary species: rat ACLAM task #9: Collaborate on selection and development of animal models SUMMARY: Rat pups are used here as a model for bronchopulmonary dysplasia, a chronic pulmonary condition associated with prolonged exposure of neonatal humans to high concentrations of oxygen. Normoxic or hyperoxic groups of pups were treated with saline, or one of two leukotriene inhibitors, zileuton or zafirlukast. Zileuton but not zafirlukast significantly ameliorated the histological changes associated with hyperoxia. QUESTIONS: 1. Which of the following histological changes in the lung are associated with hyperoxia? a. Edema b. Hemorrhage c. Alveolar macrophage influx d. Type II pneumocyte proliferation e. All of the above 2. The results of this study indicate that differences between zileuton and zafirleukast in effectiveness of decreasing pulmonary lesions of bronchopulmonary dysplasia may be due to? a. Differing pharmacodynamics (absorption) of the two drugs b. Difference in ability to suppress leukotriene B4 c. Both 3. T/F Leukotrienes are metabolites of arachidonic acid and 5-HPETE (5- hydroperoxyeicosatetraenoic acid).
  6. 6. 4. T/F Leukotrienes are elevated in broncho-alveolar lavage fluid from humans with persistent pulmonary hypertension, obstructive pulmonary disease and acute hyperoxia. 5. T/F Leukotriene modifiers have both anti-inflammatory and bronchodilator activity. ANSWERS: 1) E, 2) C, 3) T, 4) T, 5) T Bauer et al. Breeding Colony Refinement through Phenotypic and Genotypic Characterization of the SPRD-Pkdr1/Rrrc Rat Model of Polycystic Kidney Disease, pp. 193-199 Task 3 - Provide research support, information and services Task 5 - Execute IACUC veterinary responsibilities ("three Rs") Primary species - Mus musculus SUMMARY: Autosomal dominant polycystic kidney disease (ADPKD) causes focal renal cysts and eventually end-stage renal disease in humans. The SPRD-Pkdr1/Rrrc rat is used as a model for this disease, and animals that demonstrate the Cy mutation are affected. Cy/Cy rats never reach sexual maturity while Cy/+ rats demonstrate slow progression of disease similar to ADPKD (disease is most severe in males). Previously, random mating was used, and the pups were assessed at 2-3 weeks of age by kidney palpation; if any of the pups had large kidneys, this confirmed heterozygosity of both parents. This is an inefficient and expensive method that results in the euthanasia of many animals due to unwanted genotype. Thus, the purpose of this study was to evaluate the use of biochemical, ultrasound, or genetic analysis as a means to determine which animals were Cy carriers, which could result in a more efficient breeding scheme. Breedings were set up to result in either Cy/+ or +/+ offspring. The following tests and results are as follows: BUN and creatinine were measured at 4, 6, 9, and 12 weeks of age. Creatinine was not predictive of heterozygosity in either males or females. In contrast, BUN was elevated in 9-week-old het males but not females. Thus, BUN as early as 8-9 weeks can be used as a biochemical marker in males. Ultrasound was also measured at 4, 6, 9, and 12 weeks of age. At 9 weeks, all hets had enlarged kidneys and males had visible cysts. By 12 weeks, cysts were visible in both male and female hets. Genetic analysis was performed using microsatellite analysis and restriction fragment length polymorphism (RFLP). Microsatellite analysis using three markers did not correlate with Cy carrier status, while RFLP correlated 100%. Conclusion: Cy carrier status can be assessed in these rats using BUN (in males), ultrasonography and genetic testing. Genetic testing can be used to genotype both males and females as young as 14 days of age, which may be the most effective means of efficiently managing the breeding colony. QUESTIONS:
  7. 7. 1. BUN can be used to assess Cy carrier status in what sex and age of SPRD- Pkdr1/Rrrc rats? 2. At what age were cysts visible in both males and females? 3. True or False: Microsatellite analysis can be used to determine the Cy carrier status. 4. What does ADPKD stand for? ANSWERS 1. Males over 8-9 weeks of age 2. 12 weeks of age 3. False. Microsatellite analysis was not effective; RFLP assay, however, showed 100% correlation. 4. Autosomal dominant polycystic kidney disease Song et al. Brief Small Intestinal Ischemia Lessens Renal Ischemia-reperfusion Injury in Rats, pp. 200-205 Task 1 - Prevent, Diagnose, Control, and Treat Disease (Knowledge - Physiology) Primary Species - Rat SUMMARY: In humans, renal ischemia is associated with high mortality. Damage of the renal tissues is a direct result of the ischemic event (due to the lack of available oxygen), but can also be significantly increased following reperfusion of the tissues - ischemia- reperfusion (IR) insult. IR injury is one of the leading causes of the early loss of transplanted organs. “Renal ischemia leads to a series of cellular events, which may end with organ failure depending on the duration of blood deprivation.” The precise cause of IR injury is not fully understood. There are two main methods through which it is hypothesized that the damage occurs. 1) Through the direct effects of lipid peroxidation which is induced by the rapid creation of reactive oxygen species (ROS) (such as superoxide anion, hydrogen peroxide, and hydroxyl radical) when oxygen supply is restored 2) Through the indirect effects of inflammatory cells (especially neutrophils) that were activated during the period of ischemia and then enter the kidney during reperfusion. The inflammatory cells damage the renal tissues, resulting in the tissue’s production of ROS that then causes cellular death. Superoxide dismutase (SOD) and catalase (CAT) are antioxidant enzymes that participate in the detoxification of ROS. Ischemic preconditioning (IPC) is a technique whereby a brief episode of nonlethal ischemia produces protections against a subsequent detrimental ischemia-reperfusion (IR) insult. IPC has been described in the heart, brain, liver, skeletal muscle, lung, and small intestine. It has also been found that an ischemic event in one organ can have a remote protective effect on another organ. This is referred to as ‘remote preconditioning’ (rIPC). The objective of the study was to determine if rIPC of the small intestine protects the rat against renal IR injury. The ultimate goal is to find more effective ways to prevent IR injury.
  8. 8. A nephrectomy was performed on sixty-four, 250-300g Wistar rats. Fifteen days later, the anterior mesenteric artery (providing blood supply to the intestines) and/or renal arteries were occluded for varying lengths of time. After varying amounts of time the occlusion was removed and the respective tissues reperfused. Some groups of animals received more than one cycle of ischemia and reperfusion. Plasma creatinine and BUN were collected. The levels of renal malodialdehyde (MDA) and activities of SOD and CAT were determined. Renal histopathology was evaluated. It was shown that “brief small intestinal ischemia attenuates renal IR injury in rat[s], as shown by decreases in the levels of Cr, BUN, and MDA; attenuation of histopathologic change; and preservation of SOD and CAT activities…rIPC of the small intestine protects against renal IR injury via the inhibition of lipid peroxidation due to preservation of SOD and CAT activities.” In the case of kidney donation, the study suggests that “pretreatment of the living donor with small intestinal IPC prior to procurement would protect the kidney against ischemia and subsequent reperfusion injury.” QUESTIONS: 1. What is the name of the technique in which a brief episode of nonlethal ischemia produces protections against a subsequent detrimental ischemia-reperfusion (IR) insult? a. Ischemia-reperfusion bypass b. Ischemic preconditioning c. Reperfusion protection protocol 2. Ischemia-reperfusion of what tissue is increasingly recognized as a primary effector of multiple-system organ failure? a. Intestines b. Liver c. Spleen d. Heart 3. What was the primary finding of this study? Answers: 1. b. Ischemic preconditioning 2. a. Intestines 3. It was shown that brief small intestinal ischemia attenuates renal IR injury in rats. Nonhuman Primate Model Bentzel and Bacon. Comparison of Various Antihelmintic Therapies for the Treatment of Trypanoxyuris micron Infection in Owl Monkeys (Aotus nancymae), pp. 206-209 Task 1: Prevent, diagnose, control and treat disease Tertiary species: Owl monkey - Aotus nancymae SUMMARY: Trypanoxyuris microon is a pinworm that infects multiple New World nonhuman primates. It is typically clinically insignificant, but may serve as a significant variable during research data collection due to undetermined physiologic, immunologic
  9. 9. or behavioral effects. In their natural habitat, approximately half of the owl monkeys are infected with this nematode. The pinworm has a direct life cycle, similar to other pinworms. This paper compared treatment regimens with pyrantel pamoate, ivermectin and thiabendazole for effectiveness. Treatments were given on day 0 and day 14. Daily pinworm checks were done on the 19 animals for a total of 28 days. Effectiveness of treatments was evaluated using the time-to-event approach with the Kaplan-Meier method and log-rank test. Pyrantel pamoate was the most efficacious treatment with 100% clearance after one dose. This drug acts as a depolarizing neuromuscular blocking agent leading to paralysis of the worm. However, it may be ineffective against developing eggs and immature larval stages in view of a resurgence in egg detection after successful clearance of eggs. The reason for resurgence in egg detection may also have been due to reinfection as all animals on study were housed in the same room. Ivermectin is a suitable alternative however it had 80% clearance after a single dose. This compound acts as an inhibitory neurotransmitter and blocks the postsynaptic stimulation of the adjacent neuron in nematodes, causing their paralysis and death. Thiabendazole was not effective with only a 20% clearance after one dose. This data indicates that pyrantel pamoate was the most effective and rapidly acting anthelmintic for T. microon infection and it should be repeated after 1-2 weeks in combination with effective environmental sanitation. QUESTIONS: 1. Give the genus and species of the owl monkey. 2. What clinical signs can be associated with pinworm infestations? 3. Describe the life cycle of the pinworm. 4. According to this study, which is the most effective treatment for pinworms in owl monkeys? 5. What is the mechanism of action of ivermectin? 6. What is the mechanism of action of pyrantel pamoate? ANSWERS: 1. Aotus nancymae 2. It is usually asymptomatic, but can be associated with anal pruritis and irritation. 3. Infection occurs through the ingestion of larval eggs, with the adult worms colonizing the cecum, followed by the migration of gravid female worms to the perianal skin, where eggs are deposited. The life cycle is direct. 4. Pyrantel pamoate 5. Ivermectin acts as an inhibitory neurotransmitter and blocks the postsynaptic stimulation of the adjacent neuron in nematodes, causing paralysis and death. 6. Pyrantel pamoate acts as a depolarizing neuromuscular blocking agent leading to paralysis of the worm. CASE STUDY Cheeseman et al. Spontaneous Exocrine Pancreas Hypoplasia in Specific Pathogen-free C2HeB/FeJ and 101/H Mouse Pups Causes Steatorrhea and Runting, pp. 210-216 Task 1 - Prevent, Diagnose, Control and Treat Disease Primary Species: Mouse
  10. 10. SUMMARY: Spontaneous exocrine pancreas hypoplasia has not been previously reported in mice. This article is a case study of the pancreatic disorder in inbred SPF C3HeB/FeJ and 101/H strains. Clinical signs seen in pups included runting, greasy hindquarters and diarrhea. All microbiologic screenings were negative. On gross examination affected pups had undigested milk in the intestines. On histopathology, the exocrine pancreas appeared small, lacked acinar cells and no cytokeratin duct like structures. Then endocrine pancreas was unremarkable. Focal ulcerations were seen in small intestine and diffuse hepatocyte glycogen microvacuolation in the liver. Based on pathology, strain, age of onset and SPF status, a diagnosis of pancreatic hypoplasia with a complex genetic component is most likely the cause of this occurrence. QUESTIONS: 1. T or F. Based on the preliminary data, functional islet cell mass is maintained even with a loss of exocrine pancreas mass. 2. Strains observed with runting and steatorrhea include_______________ and ______________________ 3. Inherited exocrine pancreatic hypoplasia discussed in this article is also seen in which other animal: a. DSH cats b. German Shepherd Dogs c. Guinea pigs d. Nonhuman primates 4. The age of onset of disease seen commonly is: a. 5-10 days b. 10-15 days c. 14-25 days d. 14-25 weeks ANSWERS: 1. T 2. C3HeB/FeJ and 101/H mice 3. b 4. c

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