Comparative Medicine
Volume 59, Number 4, August 2009
ORIGINAL RESEARCH
Mouse Models
Nemzek and Kim. Pulmonary Inflammation and Airway Hyperresponsiveness in a
Mouse Model of Asthma Complicated by Acid Aspiration, pp. 321-331
Domain3: Research
Task: 3 Design and conduct research
SUMMARY: Several studies have indicated a strong association between asthma and
aspiration of stomach contents. However, the complex association between these
inflammatory processes has not been studied extensively in animal models. In the
present study, we developed an animal model to evaluate the inflammatory cell,
chemokine, and airway responses to asthma complicated by aspiration. The model was
produced by sensitizing mice to cockroach allergens from house-dust extracts. Mice with
asthma-like airway responses then were inoculated intratracheally with either an acidic
solution or saline. Acid aspiration increased airway hyper-responsiveness in mice with
asthma for at least 8 h. After 6 h, the combined injury caused an additive, not
synergistic, increase in airway hyper-responsiveness and neutrophil recruitment to the
airways. Although cysteinyl leukotrienes in bronchoalveolar lavage fluid were higher after
acid aspiration, treatment with a receptor antagonist before aspiration did not diminish
airway hyper-responsiveness. Vagal mechanisms reportedly mediate airway responses
in acid aspiration; however, pretreatment with an anticholinergic agent did not reduce
airway responses to acid. These results are consistent with an effective model of the
acute effects of aspiration on the allergic lung. Further studies could examine how
various forms of aspiration influence the severity of asthma.
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There is a strong association between asthma and aspiration of stomach contents
and the prevalence of gastroesophageal reflux in some patients is > 50%.
Clinical studies have shown that acid in the esophagus promotes neurologic
responses leading to bronchoconstrictionimpaired airway function.
There are well-established models for both asthma and aspiration but the patterns of
inflammation are complex.
Study design: Induced asthma using an extract containing cockroach allergens
(Blattella germanica (Bla g1) and 2 (Bla g2) and confirmed asthma-like response by
measuring airway hyper-responsiveness by whole-body plethysmography and
methacholine challenge.
A plethysmograph is an instrument for measuring changes in volume within an organ
or whole body (usually resulting from fluctuations in the amount of blood or air it
contains).
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A bronchial challenge test is a medical test used to assist in the diagnosis of
asthma.[1] The patient breathes in nebulized methacholine or histamine. Thus the test
may also be called a methacholine challenge test or histamine challenge test
respectively. Both drugs provoke bronchoconstriction, or narrowing of the airways.
The degree of narrowing can then be quantified by spirometry. People with preexisting airway hyper-reactivity, such as asthmatics, will react to lower doses of drug.
‘Penh’ is an index of airway hyper-reactivity (Penh= (peak expiratory flow/peak
inspiratory flow) – ((expiratory time / time for expiration of 65% volume) – 1). It is a
unitless parameter derived mathematically from the respiratory waveform produced
by whole-body plethysmography. It indicates changes in airway resistance have
occurred. Its use for measuring airway resistance is controversial because it is
influenced by breathing patterns.
Results: Consistent with previous research using this asthma model: Increasing
concentrations of methacholine (0 to 50 mg/ml) resulted in incremental increases in
mean Penh. Mice showed no signs of distress, no change in weight or activity. After
mice underwent asthma protocol, they were made to aspirate either saline or an
acid solution. Previous studies show inflammatory responses to aspiration increase
until 8 hours post administration as also seen in this study. Compared to
intratracheal saline alone, acid significantly increased airway responses to
methacholine and when allergy induction preceded acid aspiration, responses were
further increased.
Mice given intrathecal acid alone did not show a significant change in total BAL fluid
cell counts but had an increase in neutrophil counts vs. those given saline alone.
However, mice with pre-existing asthma and saline inoculation had increased
macrophages, neutrophils, and eosinophils compared to mice without asthma.
The inflammatory cell, chemokine MIP2 alpha, was significantly higher in the
asthma-acid group’s BAL fluid vs. the asthma-saline group.
Advantages to this study: Examined the effects of acid aspiration with asthma
induced by clinically relevant (cockroach) allergens; All mice recovered to allow
pulmonary changes to develop under more physiologic conditions vs. other studies
where they’ve euthanized after asthma induction.
Effects of combined injury (asthma + acid) were additive rather than synergistic. The
responses were more robust if aspiration occurred within 24 hours rather than 48
hours.
The airway hyper-responsiveness after acid aspiration may be related to vagal nerve
stimulationacid in the esophagus can trigger neurogenic inflammation and
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bronchoconstriction in anesthetized animals; it is a greater response if acid is in the
larynx or trachea. However, in this study atropine only negligible attenuated
bronchoconstriction.
Overall, this study developed a murine model of asthma exacerbated by acid
aspiration (thus, combining 2 well-established protocols) that lead to lung
inflammation in unanesthetized animals. Also, despite aspiration being mediated by
the vagal nerve, the results here suggest that neither an anticholingergic agent
(atropine) nor a leukotriene receptor antagonist provide treatment in acute
bronchoconstriction.
QUESTIONS:
1. T/F There is a strong association between asthma and aspiration of gastric contents
2. What is the definition of a plethysmograph?
3. What clinically relevant allergen was used in this study to induce asthma?
4. What is the unit of measure of airway hyper-reactivity?
ANSWERS:
1. TRUE
2. It is an instrument for measuring changes in volume within an organ or whole body
(usually resulting from fluctuations in the amount of blood or air it contains).
3. Cockroach allergen
4. The ‘penh’ is an index of airway hyper-reactivity
Dadi et al. Decreased Growth Factor Expression through RNA Interference
Inhibits Development of Mouse Preimplantation Embyros, pp. 331-338
Domain 3: Research
Primary species: Mouse
SUMMARY: Regulation of embryo development is mediated by numerous growth factors
including epidermal growth factor (EGF) and transforming growth factor α (TGFα), and
their cognate receptor (EGFR). In contrast to naturally derived mouse embryos, growth
factor gene expression fails to increase significantly above baseline in cloned mouse
embryos. This study utilized RNA interference (RNAi) to decrease expression of growth
factors in preimplantation mouse embryos and assess the extent to which these factors
are crucial for embryo development. Gene specific short interfering RNA (siRNA) to
EGF, TGFα, EGFR, or combined EGF and TGFα was administered to four experimental
groups of 1-cell stage embryos. Additionally, a negative control group with no siRNA
treatment, a positive control group with noninhibitory siRNA, and an untreated cloned
embryo group were used. After treatment with siRNA, expression of EGF, TGFα, EGFR,
and EGF and TGFα together were significantly decreased at all stages of development
compared with controls.
Additionally, protein expression levels after treatment
with siRNAs were similar to expression levels in cloned embryos. Fewer 1-cell embryos
developed to blastocysts after treatment with siRNA to EGF and TGFα than did controls.
After treatment with siRNA to EGFR or combined EGF and TGFα even fewer survived,
similar to cloned embryos. Compared with the mean number of apoptotic cells seen in
control embryos, the mean number of apoptotic cells was significantly greater in all
treatment groups. The mean number and percentage of apoptotic cells in cloned
embryos was similar to those treated with siRNA to EGFR or combined EGF and TGFα.
Finally, the mean number of cells in blastocysts was decreased significantly in all
treatment groups compared with controls, and was similar to the number of cells
measured in cloned embryos. Results support the authors’ hypothesis that EGF
and TGFα are crucial for embryo survival and development, and that dysregulated
expression of growth factors is associated with poor development in cloned mouse
embryos.
QUESTIONS:
1. What is does RNAi stand for and how was it used in this study?
2. T/F. Expression of growth factors EGF and TGFα are increased in preimplantation
cloned mouse embryos leading to poor development.
ANSWERS:
1. RNA interference; posttranscriptional gene silencing for genes encoding specific
growth factors
2. 2. False
Brooks and Conrad. Isoproterenol-Induced Myocardial Injury and Diastolic
Dysfunction in Mice: Structural and Functional Correlates, pp. 339-343
Primary Species: Mouse
Task 10: Design and Conduct Research (4±1%)
K1, K2, K3, K7
SUMMARY: The objective of this study was to determine whether a simple, noninvasive
method involving administration of isoproterenol could be used to produce myocardial
injury and cardiac dysfunction in the mouse heart with a low incidence of mortality. Adult
Swiss-Webster mice were injected with isoproterenol (100 mg/kg SC) once daily for 5 d.
Myocardial histology and left ventricular (LV) function were assessed 10 to 14 d after the
last isoproterenol injection in 14 surviving isoproterenol-treated mice and 15 salinetreated control mice. Left ventricular systolic and diastolic pressures were evaluated in
vitro by means of isovolumically contracting, perfused Langendorff preparations.
Isoproterenol induced marked endocardial injury, associated with hypertrophy of
surviving myocytes, and an increase in myocardial fibrosis (collagen types I and III
according to picrosirius red microscopy). The hearts from isoproterenol-treated mice
demonstrated decreased LV compliance, as evidenced by an upward shift in the
diastolic pressure-volume relationship, with normal LV systolic function. Isoproterenol
administration provides a simple, noninvasive means to induce endocardial injury and
diastolic dysfunction without significant impairment of systolic function. This model has a
low incidence of mortality and may be useful to assess the effects of gene or stem cell
therapy on cardiac dysfunction without the potential confounding effects of invasive
procedures.
Background: The availability of genetically altered mice provides an opportunity to
assess the structural and functional role of specific proteins that are involved in
myocardial injury and potential therapeutic interventions. In general, techniques to
induce myocardial injury and pathologic hypertrophy in the mouse have required surgical
procedures such as ligation of the coronary artery, banding of the aorta, or implantation
of an osmotic minipump to infuse β-adrenergic agonists, with associated risk of morbidity
or mortality. Moreover, in vascular occlusion models, delivery of gene or stem cell
therapy to damaged myocardium might require additional surgery because of the need
for direct injection. For these reasons, a relatively noninvasive murine model that
induces discrete myocardial injury in the presence of a patent coronary circulation, with a
low incidence of mortality, would be of interest. The primary purpose of the present
study was to define the functional consequences of the adverse structural changes
induced in the mouse heart by multiple isoproterenol injections. The primary purpose of
the present study was to define the functional consequences of the adverse structural
changes induced in the mouse heart by multiple isoproterenol injections.
Materials and Methods: Pages 339 to 340.
Results: See Tables 1 and 2. See Figures 1 – 3. Pages 341, 342.
Discussion: The author’s primary finding in this study is that myocardial injury and
fibrosis induced by repetitive administration of isoproterenol in the mouse heart is
associated with decreased LV compliance, with marked increase in LV filling pressure
for any given volume, in association with hypertrophy of the surviving myocardium and
no significant impairment of overall systolic function. The author’s state that this model
may be of interest with regard to the clinical syndrome of LV diastolic dysfunction and
heart failure, in contrast to the myocardial infarction model, in which the primary
impairment is related to systolic function.
Conclusions:
1. Isoproterenol administration affords a simple, noninvasive means for inducing
myocardial injury and diastolic dysfunction in the mouse heart,
2. It has a low incidence of mortality and without the potentially confounding effects of
invasive procedures.
The author’s state that this model may be useful in assessing the therapeutic effects of
pharmacologic agents and gene or stem cell therapy on LV diastolic dysfunction in
murine model of myocardial injury.
QUESTIONS:
1. The Masson trichrome and Picrosirus red stains were used to stain histological
samples of the mouse hearts for what protein?
2. The picrosirius polarization techniques were used to differentiate between which two
types of collagen?
3. What best defines the coat color of the out bred Swiss–Webster mouse?
a. Agouti
b. Brown
c. Black
d. Albino
3. Cross-sections of LV from isoproterenol-treated hearts demonstrated a marked
increase in the collagen network of the myocardium. The red–yellow- (type I) and
green- (type III)
ANSWERS:
1. Collagen
2. The red–yellow- (type I) and green- (type III)
3. d. Albino
Rat Models
Andersen et al. Altered Sleep Patterns and Physiologic Characteristics in
Spontaneous Dwarf Rats, pp. 344-349
Domain 1: Management of Spontaneous and Experimentally Induced Diseases
and Conditions
Species: Primary- Rat
SUMMARY: This study examined the hormone profile, sleep pattern, and serum
ceruloplasmin (Cp) levels of a newly identified spontaneous dwarf rat and normal rats to
better characterize the physiopathologic process of low GH. Dwarf rats are commonly
used for studying various biological events associated with pituitary dwarfism. Some of
these animals have a selective absence of growth hormone (GH) due to a point mutation
in the GH gene which mimics GH deficiency in humans. GH is released according to
circadian rhythm. Dwarf rats have altered sleep patterns suggesting that GH deficiency
impairs sleep. Ceruloplasmin is a copper containing glycoprotein enzyme, whose
function is not fully understood, but has been suggested to be an acute phase protein.
Increases in Cp are seen during pregnancy, inflammation and trauma. In this study,
dwarf rats were found to have marked fragmented sleep patterns, less paradoxical
sleep, lower GH, testosterone and Cp levels than normal rats. The low Cp level
demonstrates the importance of GH in Cp expression.
QUESTIONS:
1. Dwarf rats can be used for a model of
a. Pituitary dwarfism
b. Physiologic role of GH
c. Physiologic role of progesterone
d. A and b
e. All of the above
2. Ceruloplasmin is a copper containing glycoprotein that increases during the
following:
a. Pregnancy
b. Trauma
c. Inflammation
d. All of the above
ANSWERS :
1. d
2. d
Cho et al. Temporal Changes of Angiopoietins and Tie2 Expression in Rat Lungs
after Monocrotaline-Induced Pulmonary Hypertension, pp. 350-356
Task 3 – Provide Research Support, Information, and Services
Primary Species - Rat
SUMMARY: Pulmonary hypertension (PH) is known to cause pathological angiogenesis
in lung tissue. A study was conducted to examine the temporal expression of several
angiogenesis related molecules in a rat model of monocrotaline induced PH.
Monocrotaline induced vascular hypertrophy and hyperplasia of pulmonary vessels
within 1 week following drug administration, and both hypertrophy and hyperplasia
increased over the 3 week duration of the experiment, thus indicating the presence of
persistent and progressing pulmonary hypertension. Expression of other angiogenesis
related molecules, vascular endothelial growth factor (VEGF), endothelial nitric oxide
synthase (eNOS), inducible nitric oxide synthase (iNOS) and heme oxygenase 1 (HO1)
steadily increased over the course of PH development. Expression of the molecules
angiopoietin (Ang) 1, and Ang 2 increased over the course of the experiment while
expression of the Ang receptor (Tie2) decreased. Ang1 and Ang2 compete for receptor
binding on Tie2 and are antagonistic to each other, with Ang1 activating Tie2 and
generally producing compensatory vascular remodeling and Ang2 blocking Tie2
activation and causing endothelial instability. Perhaps to most significant result is the
ligand and receptor ratios (Ang1:Tie2 and Ang2:Tie2) where progressing PH was
associated with a higher Ang2:Tie2 ratio than Ang1:Tie2 indicating Tie2 inactivity as the
predominant effect, although both Ang1:Tie2 and Ang2:Tie2 ratios were elevated as
compared to placebo treated control animals indicating both Ang1 and Ang2 are
involved in PH and associated vascular remodeling.
QUESTIONS:
1. What are some common pulmonary histopathological changes associated with
pulmonary hypertension?
2. What is the significance of examining Ang1:Tie2 and Ang2:Tie2 ratios rather than
simply protein expression in the current report?
ANSWERS:
1. Arterial hyperplasia, and hypertrophy of vessel walls
2. Ang1 and Ang2 compete for a single receptor (Tie2). Ang1 and Ang2 also have
opposite effects on Tie2 (Ang1 activates while Ang2 does not). Therefore, an
examination of the ratios provides a better indication of the overall effect of Ang1 and
Ang2 in vivo.
Rabbit Model
Jean et al. Cyclosporine-Induced Gingival Overgrowth in New Zealand White
Rabbits (Oryctolagus cuniculus), pp. 357-362
Task 1
Primary Species: Rabbits
SUMMARY: Cyclosporine induced gingival overgrowth (CIGO) is a well documented
adverse effect of cyclosporine treatment in humans and dogs. A high incidence of
ptylism, and facial dermatitis occurred in rabbits in a retinoblastoma study.
Materials and Methods: N=18 rabbits which were involved in a retinoblastoma study.
They received daily Cyclosporin to induce immunosuppression and facilitate tumor
growth. Rabbits that experienced clinical signs would receive dose reduction of
cyclosporine from 15 mg/kg to 10 mg/kg. If clinical signs did not resolve within one
week, the rabbits received azithromycin 62.5 mg SID PO q 7 days.
Animals underwent clinical observations and necropsy. The skulls were harvested for
gingival measurements. Gingival tissues were taken for histopathology.
Results: There was a 100% incidence of CIGO in the rabbits that received 15 mg/kg
cyclosporine SID for 14 days or more.
Clinical signs included ptylism, inappetence, or dermatitis of the muzzle and neck.
Hyperemia or thickening of the gingival around the incisors occurred in severe cases.
All but 2 rabbits responded to decreasing the cyclosporine dose. The remaining two
rabbits responded to Azithromycin.
Gross pathology revealed bilateral thickening of the molar maxillary and mandibular
gingiva. Histology revealed increased numbers of degenerate and viable keratinocytes
in the stratified squamous epithelium.
QUESTIONS:
1. How is CIGO treated?
2. CIGO occurs more (anteriorly or posteriorly) in the rabbit than in humans?
ANSWERS:
1. Reducing the cyclosporine dose and or azithromycin
2. Posteriorly
Ferret Model
Nemelka et al. Immune Response to and Histopathology of Campylobacter jejuni
Infection in Ferrets (Mustela putorius furo), pp. 363-371
Primary species: Ferrets (Mustela putorius furo)
SUMMARY: Campylobacter jejuni is one of the most common enteric bacterial
pathogens globally. The mechanism by which C. jejuni causes diarrheal disease is
poorly understood. The goal of this study was to determine the virulence and antigenspecific immune responses of C. jejuni strain CG8421 in ferrets as a possible future
challenge strain in human vaccine efficacy studies. Unlike other small animals, naïve
ferrets (< 11 wk) intragastrically inoculated with C. jejuni have shown resistance to
disease when rechallenged with a homologous strain, but show no resistance to
infection (similar to infection in humans.) C. jejuni CG8421 was isolated from a case of
dysentery in Thailand, and has a lipooligosaccharide core that lacks ganglioside
mimicry. C. jejuni strain 81-176 was used as an infectivity reference strain.
Pathogen-free female domestic ferrets of 5.5-6 weeks of age were obtained and
randomized into 5 groups of 4 animals (3 infected, 1 control). The 5 groups were
euthanized on days 1, 2, 3, 6, and 9. Orogastric feeding tube was used to inoculate
animals with C. jejuni or PBS only (control). Fecal samples were collected pre-infection
and days 1-4, 6, and 9 post-infection. Cardiac blood (7-14ml) was collected in a syringe
immediately before performing a full necropsy.
Ferrets infected orally with C. jejuni CG8421 developed diarrhea at rates and illness
patterns comparable to those reported for humans. The inflammatory nature of the
diarrhea was confirmed by the presence of lactoferrin and blood in stools; lactoferrin was
a more sensitive indicator than occult blood. The presence of C. jejuni by microbiologic
isolation and immunohistochemical reactivity in the liver within 24 hours of inoculation
did not elicit a detectable inflammatory response, as verified by lack of C-reactive
protein, and no histopathologic lesions were seen in any liver samples. The duration of
diarrhea and infection rates associated with CG8421 were similar to those for strain 81176 in ferrets. Both systemic and mucosal immune responses (serum and fecal IgA and
IgG) were detected and appeared to be functional in controlling diarrhea, while fecal
excretion of C. jejuni continued; diarrhea resolved spontaneously within 3 days of
infection, but C. jejuni was excreted throughout the study. The colons of infected
animals showed damage of the brush border in areas adjacent to bacteria that appeared
to be bound to epithelial cells, and numerous neutrophils were present within the
epithelial layer and lamina propria (which may explain the clinical neutropenia due to
possible sequestering of neutrophils in the intestinal epithelium.) Results confirm the
virulence of C. jejuni strain CG8421 and underscore the usefulness of the ferret model
for studies of C. jejuni pathogenesis.
QUESTIONS:
1. Do the authors believe that C. jejuni strain CG8421 would be appropriate as a future
challenge strain in vaccine efficacy studies?
2. What is the importance of strain CG8421 having a lipooligosaccharide core that lacks
ganglioside mimicry?
ANSWERS:
1. Yes. The authors feel that this study has shown that C. jejuni strain CG8421 has
similar infectivity to other strains. The authors also feel that the ferret shows promise
as an appropriate research model in that they show similar pathogenesis of disease
as human cases of C. jejuni.
2. Most strains of C. jejuni contain lipooligosaccharides that mimic human gangliosides
structurally. Antibodies against these lipooligosaccharide structures lead to an
autoimmune response, resulting in Guillain-Barré syndrome. The absence of
ganglioside mimicry is predicted to reduce the risk of Guillian-Barré syndrome.
Swine Model
Chen et al. Cloning of the Full-Length cDNA of Porcine Antithrombin II and
Comparison with its Human Homolog, pp. 372-377
Domain 3: Research, T1. Facilitate or provide research support, K3. Animal models
Primary Species: Pig
SUMMARY: Antithrombin III (ATIII) is a single-chain glycoprotein found in mammalian
plasma that inhibits thrombin and other serine proteinases involved in the blood
coagulation cascade, such as factor IX, factor X, and plasmin. ATIII is considered the
most powerful serine proteinase inhibitor and the most important contributor to the
anticoagulation system.
A genetic comparison of porcine ATIII to human ATIII revealed many areas of
conservation between them. Porcine ATIII has 87.67% nucleotide and 89.06% amino
acid identity with human ATIII . This is the first time the porcine ATIII has been fully
sequenced. Assays of porcine and human plasma showed no remarkable differences
between the two in regard to ATIII activity. This information helps formulate a better
understanding of the activity of porcine ATIII in man when a pig-to-human transplant has
occurred.
QUESTIONS:
1. What is true ?
A. Porcine ATIII has less biological activity than human ATIII
B. Porcine ATIII speeds clot formation
C. There is little similarity between human and porcine ATIII
D. None
2. In which field are the findings from the study applicable?
A. Transgenics
B. Proteonomics
C. Xenotransplantation
D. None
ANSWERS:
1. D
2. C
Canine Model
Carlstrom et al. Inadvertent Propagation of Factor VII Deficiency in a Canine
Mucopolysaccharidosis Type I Research Breeding Colony, pp. 378-382
Species: Canine (primary)
Role delineation: Task 1-Prevent, Diagnose, Control, And Treat Disease- Clinical
Medicine
SUMMARY: The authors report on the discovery and characterization of FVII deficiency
that was unknowingly propagated within a beagle breeding colony maintained for
mucopolysaccharidosis type I (MPS I) research. Factor VII deficiency is an autosomal
recessive hemostatic disorder, and the mutation is reportedly found in increased
frequencies in beagles, Alaskan malamutes, Alaskan klee kais, Airedale terriers, giant
schnauzers, Scottish deerhounds, and mixed breed canines. The condition is most
often asymptomatic, but can predispose to excessive bleeding after surgery or trauma,
hematoma formation, body cavity bleeding, and persistent uterine and vaginal
hemorrhage (very important in a breeding colony). Affected animals can be treated by
transfusions with fresh plasma or blood, or administration of recombinant activated
human, but any treatment offers only a temporary solution as the half-life of FVII protein
is only 3 to 4 h and, in canines, treatment with human proteins raises concern about
antibody responses to those proteins, thus potentially limiting further therapy. The
maintenance of genetic diseases in research colonies is due to a founder effect by which
allelic frequencies may be skewed upward compared to those in the general population
because of insufficient genetic outcrosses, resulting from economic constraints and
considerations such as the inbreeding needed with a recessive condition (e.g., the MPSI
condition for the colony in question). Underlying genetic disease conditions, and
especially FVII deficiency, should be a primary concern when developing research
colonies composed of beagle breeding stock. This institution referenced in this article
developed and will henceforth use a PCR-based diagnostic assay to screen all potential
breeding stock to prevent similar occurrences of FVII deficiency in their future beagle
research colonies.
QUESTIONS:
1. Which blood clotting disorder was reported as inadvertently propagated through a
founder effect in a beagle MPS I research breeding colony?
a. Alexander’s disease, due to a factor VII deficiency
b. Hemophilia A, due to a factor VIII deficiency
c. Hemophilia B, due to a factor IX deficiency
d. Hemophilia C, due to a factor XI deficiency
2. What type of mutation is factor VII deficiency?
a. Autosomal dominant
b. Autosomal recessive
c. Sex-linked dominant
d. Sex-linked recessive
3. Which canine breed is not reported as having an increased incidence of factor VII
deficiency?
a. Alaskan malamutes
b. Airdale terriers
c. Beagles
d. Doberman pinschers
e. Giant schnauzers
ANSWERS:
1. a. Alexander’s disease, due to a factor VII deficiency
2. b. Autosomal recessive
3. d. Doberman pinschers
Nonhuman Primate Model
White et al. Prevalence of Viremia and Oral Shedding of Rhesus Rhadinovirus and
Retroperitoneal Fibromatosis Herpesvirus in Large Age-Structured Breeding
Groups of Rhesus Macaques (Macaca mulatta), pp. 383-390
Task 1, K7
Species: Primary Rhesus Macaque (Macaca mulatta)
SUMMARY: Retroperitoneal fibromatosis herpesvirus is considered the macaque
analogue of Kaposi sarcoma-associated herpesvirus (KSHV) in humans. There are
histological similarities between RFVH and KS lesions in humans co-infected with KSHV
and HIV. Recently another gamma herpesvirus, Rhesus Rhadinovirus (RRV) has been
shown to be associated with a form of lymphoma and retroperitoneal fibromatosis in
rhesus macaques co-infected with SIV, making them a promising animal model for
KSHV study.
A cross sectional study looked at breeding colonies of rhesus macaques maintained at
The California National Primate Research Center and determined the prevalence of
RRV and RFHV. Blood samples and saliva swabs were collected from a total of 90
animals. PCR, immunofluorescent assay, Western blots, and determination of cell copy
numbers were performed. The results of these diagnostic tests were compiled to
estimate the actual prevalence of viremia and oral shedding of both these herpesviruses.
RRV was determined to be significantly more prevalent than RFHV, and both were found
to be more prevalent in younger animals. RRV-specific DNA detection was detected in
both blood and saliva in 40% of the macaques, 24% in blood only, and 16% in saliva
only. RFHV-specific DNA was detected in both blood and saliva in 10% of the
macaques, 6% in blood only, and 29% in saliva only. Co-infection with RRV and RFHV
was found in 42% of the macaques tested. No animal tested negative for rhadinovirus
antibody according to the immunofluorescent antibody test, but this test was not able to
distinguish between the different viruses. Based on their results, both RRV and RFHV
were determined to be highly endemic in socially housed rhesus macaques. And this
close physical contact afforded by typical nonhuman primate housing plays an important
role in transmission of these viruses.
QUESTIONS:
1. Both RRV and RFHV are what type of herpes virus?
a. Beta
b. Gamma
c. Alpha
2. Which virus was found to be more prevalent in this study?
a. RRV
b. RFHV
c. Both were equally prevalent
3. True or False: Both RRV and RFHV are shed in oral secretions, and close physical
contact of normal nonhuman primate group behavior may be significant in the
transmission of these viruses.
ANSWERS:
1. b
2. RRV
3. True