Diagnostic exercise: infertility in two chimeric mice.
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Animals↗
Biomedical subjects
J G Fox
Publications and source records attributed to J G Fox.
Helicobacter and liver disease.
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Animals↗
Processing and proliferative effects of human progastrin in transgenic mice.
Incompletely processed gastrins have been postulated to play a role in growth of the gastrointestinal tract, but few studies have examined the effects of progastrin on mucosal proliferation in vivo. Human gastrin gene expression and progastrin processing were therefore studied in transgenic mice containing a human gastrin (hGAS) minigene, and compared to processing in mice bearing an insulin gastrin (INS-GAS) transgene that overexpresses amidated gastrin. Progastrin processing was studied using region-specific antisera and radioimmunoassays, biosynthetic labeling, immunoprecipitation, and HPLC. Proliferative effects due to overexpression of processed and unprocessed gastrin in INS-GAS and hGAS mice, respectively, were determined using routine histology and BrdU incorporation. The pancreatic islets of INS-GAS mice were able to produce carboxyamidated G-17, resulting in a twofold elevation of serum amidated gastrin, marked thickening of the oxyntic mucosa, and an increased BrdU labeling index (LI) of the gastric body. In contrast, livers of adult hGAS mice expressed abundant human gastrin mRNA and human progastrin but were unable to process this peptide to the mature amidated form, resulting in markedly elevated serum progastrin levels and normal amidated gastrin levels. Nevertheless, there was a marked increase in the BrdU labeling index of the colon in hGAS mice (LI 7.46+/-1.90%), as well as in INS-GAS mice (LI 6.16+/-1.17%), compared to age-matched, wild type control mice (LI 4.01+/-0.98%, P < 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo.
Animals↗
Clinical and pathologic findings in ferrets with lymphoma: 60 cases (1982-1994).
OBJECTIVE: To examine clinical and pathologic findings in 60 ferrets with lymphoma. DESIGN: Retrospective case series. ANIMALS: 60 ferrets in which the diagnosis of lymphoma had been confirmed by means of histologic examination of biopsy or necropsy specimens. PROCEDURE: Information including age, sex, coat color, history, clinical signs, clinicopathologic abnormalities, treatment, outcome, and results of histologic examination of biopsy and necropsy specimens were retrieved from medical records of ferrets with spontaneous lymphoma examined between 1982 and 1994 at the Massachusetts institute of Technology or private veterinary practices in 10 states. Classification of lymphoma was assigned according to the National Cancer Institute's working formulation for non-Hodgkin's lymphomas. Chi 2 Trend analysis was used to determine whether age was associated with history, clinical signs, hematologic abnormalities, stage, histologic grade, or outcome. RESULTS: Acute onset, mediastinal mass, lymphocytosis, and multicentric distribution were linked with younger ferrets, and lymphopenia and survival longer than 2 months after diagnosis was associated with older ferrets. Twenty percent of ferrets in this study had cohabitated with another ferret with lymphoma. Chemotherapeutic efficacy was not evaluated. CLINICAL IMPLICATIONS: Clinical and pathologic features linked with age should be considered when evaluating diagnostic and therapeutic options for ferrets with lymphoma.
Animals↗
Evaluation of hollow fiber bioreactors as an alternative to murine ascites production for small scale monoclonal antibody production.
The objective of this study was to compare monoclonal antibody production in hollow fiber bioreactor systems and murine ascites to determine the feasibility of the bioreactor system as a potential alternative to the use of mice. Three hybridoma cell lines were grown in each of three different hollow fiber bioreactor systems and in groups of 20 mice. Mice were primed with 0.5 ml pristane intraperitoneally 14 days prior to inoculation of 1X10(6) hybridoma cells. Each mouse was tapped a maximum of three times for collection of ascites. Ascites volumes and daily clinical observations were recorded. Bioreactors were harvested three times weekly for 65 day and were monitored by cell counts, cell viability and media glucose consumption. Time and materials logs were maintained. The total quantity of monoclonal antibody produced in 20 mice versus the mean production for the three different bioreactors in 65 days was as follows: cell line 2B11, 455 mg vs. 168 mg; cell line 3C9, 446 mg vs. 565 mg; and cell line RMK, 997 mg vs. 1023 mg. Mean monoclonal antibody concentration ranged from 4.07 to 8.37 mg/ml in murine ascites, and from 0.71 to 11.10 mg/ml in hollow fiber bioreactor system. Although time and material costs were generally greater for the bioreactors, these results suggest that hollow fiber bioreactor system merit further investigations as potentially viable in vitro alternatives to the use of mice for small scale (< 1 g) monoclonal antibody production.
Animals↗
Identification of a DNA segment in ferret Aleutian disease virus similar to a hypervariable capsid region of mink Aleutian disease parvovirus.
A 401bp DNA fragment of ferret Aleutian disease virus (ADV) was amplified using PCR primers spanning a hypervariable region of mink ADV capsid sequence. The amplified fragment was 88-89% homologous to the same region of previously known sequence of three different strains of mink ADV, however, as low as 54% homology was observed when compared with a 39bp segment known as hypervariable region. Within the predicted 13 amino acid hypervariable region, the ferret ADV sequence differed at 6 positions from the wild type mink Utah1 strain. Three amino acids Gln289, Glu293 and Thr295 in this region were common to the pathogenic ferret ADV, mink Utah1 and ADVK strains, but differed from the cell culture adapted nonpathogenic mink strain ADVG suggesting that these three conserved residues may have some functional significance.
Aleutian Mink Disease Virus↗
Local immune response in Helicobacter pylori-infected cats and identification of H. pylori in saliva, gastric fluid and faeces.
Helicobacter pylori-infected cats were screened by culture and polymerase chain reaction (PCR) for the presence of H. pylori in salivary secretions, gastric juice, gastric tissue and faeces. H. pylori was cultured from salivary secretions in six of 12 (50%) cats and from gastric fluid samples in 11 of 12 (91%) cats. A 298 base pair polymerase chain reactions (PCR) product specific for an H. pylori 26000 MW surface protein was amplified from dental plaque samples from five of 12 (42%) cats and from the faeces of four of five (80%) cats studied. Analyses of serum and mucosal secretions by enzyme-linked immunosorbent assay (ELISA) revealed an H. pylori-specific immunoglobulin G (IgG) response, and elevated IgA anti-H. pylori antibody levels in salivary and local gastric secretions. Immunohistochemical analyses of gastric tissue revealed the presence of IgM+ B cells assembled into multiple lymphoid follicles surrounded by clusters of CD4+ and CD8+ T cells. The lamina propria also contained single cells or aggregates of IgA+ and IgM+ B cells. These observations show that H. pylori can be identified in feline mucosal secretions, and that a localized IgA immune response develops in gastric tissue of H. pylori-infected cats. The findings suggest a zoonotic risk from exposure to personnel handling H. pylori-infected cats in vivaria.
Animals↗
Hypertrophic gastropathy in Helicobacter felis-infected wild-type C57BL/6 mice and p53 hemizygous transgenic mice.
BACKGROUND & AIMS: Helicobacter pylori infection causes gastritis and peptic ulcers and is linked epidemiologically to gastric cancer. To analyze host genetic factors and the influence of Helicobacter on cell proliferation, we used an inbred and p53 hemizygous mouse model of Helicobacter felis-induced gastritis. METHODS: H. felis was inoculated by gastric intubation into SPF C57BL/6 wild-type and p53 hemizygous mice that were followed up for 1 year and compared with uninfected controls of the same genotype using histology, proliferating cell nuclear antigen (PCNA) staining, and 5-bromo-2'-deoxyuridine (BrdU) analysis. RESULTS: Infected animalls developed sustained anti-H. felis serum immunoglobulin G antibody responses. Six months after infection, both wild-type and p53 hemizygous mice showed active chronic inflammation and marked mucosal hyperplasia compared with uninfected controls. One year after infection with H. felis, the wild-type and p53 hemizygous mice showed severe adenomatous and cystic hyperplasia of the surface foveolar epithelium. BrdU uptake and PCNA staining were markedly increased in both sets of infected mice compared with controls. Infected p53 hemizygous mice had a higher proliferative index than the infected wild-type mice. CONCLUSIONS: H. felis can induce a hypertrophic gastropathy in the C57BL/6 genotype; loss of one p53 allele, although insufficient to initiate carcinogenesis at 1 year, enhances the proliferative index, which may lead to an increased risk of cancer induction.
Alleles↗
Helicobacter trogontum sp. nov., isolated from the rat intestine.
A new Helicobacter species that colonizes the colonic mucosa of Wistar and Holtzman rats was isolated and characterized. This bacterium was gram negative, its cells were rod shaped with pointed ends, and its protoplasmic cylinder was entwined with periplasmic fibers. It was catalase and oxidase positive, rapidly hydrolyzed urea, and was susceptible to metronidazole and resistant to cephalothin and nalidixic acid. The new organism was microaerophilic and grew at 42 degrees C, a feature that differentiates it from two other murine intestine colonizers, Helicobacter hepaticus and Helicobacter muridarum. On the basis of 16S rRNA sequence analysis data, the new organism was identified as a Helicobacter species that is most closely related to H. hepaticus. This bacterium is named Helicobacter trogontum. The type strain is strain LRB 8581 (= ATCC 700114).
Animals↗
Natural and experimental Helicobacter mustelae reinfection following successful antimicrobial eradication in ferrets.
BACKGROUND: Recrudescence or reinfection may occur after eradication of Helicobacter pylori in humans. MATERIALS AND METHODS: We used the ferret Helicobacter mustelae model to investigate the effect of prior infection and eradication on reinfection by experimental and natural routes. Two groups of ferrets with naturally acquired H. mustelae infection were treated with an eradication protocol using amoxicillin, metronidazole, and bismuth subsalicylate. The ferrets were monitored for recrudescence by repeated cultures of endoscopic gastric mucosal biopsies. The ferrets were challenged at 17 months (group I) and 6 months (group II) after eradication with a strain of H. mustelae having a distinctive restriction endonuclease analysis pattern. The eradication protocol was repeated to eliminate the infection produced by experimental challenge. The ferrets were then cohoused intermittently with naturally infected ferrets. RESULTS: The original H. mustelae infection was successfully eliminated by the eradication protocol. No recrudescence was observed in group I for 12 months nor for 3 months in group II after eradication. All ferrets became persistently reinfected with the challenge strain. The infection from the challenge strain was eradicated successfully. No ferrets in group I and all ferrets in group II became infected through cohousing. CONCLUSIONS: These results suggest that though prior infection with H. mustelae may confer some protection against reinfection, such protection is not universal in all circumstances; that susceptibility to reinfection by contact with infected animals varies between individuals; and that age may be a factor in this individual variability. These results are applicable to studies of reinfection after eradication of H. pylori in humans.
Amoxicillin↗
Use of PCR and culture to detect Helicobacter pylori in naturally infected cats following triple antimicrobial therapy.
Helicobacter pylori causes gastritis and peptic ulcers and is linked to gastric cancer. Domestic cats from a commercial source were found to be naturally infected with H. pylori, and studies were undertaken to eradicate H. pylori from infected cats by using triple antimicrobial therapy. Eight cats infected with H. pylori were used in the study. Six cats received a 21-day course of oral amoxicillin, metronidazole, and omeprazole, and two cats served as controls. Two weeks and 4 weeks posttreatment (p.t.), all six treated cats were negative at several sites (saliva, gastric juice, and gastric mucosa) for H. pylori by culture. However, as determined by PCR with primers specific for the 26-kDa product, the majority of cats at 2 and 4 weeks p.t. had gastric fluid samples which were positive for H. pylori and three of three cats at 2 weeks p.t. had dental plaque which was positive for H. pylori. At 6 weeks p.t., all six cats had H. pylori-negative cultures for samples from several gastric sites taken at necropsy, and only one cat had H. pylori cultured from gastric juice. PCR analysis revealed that five of six cats had H. pylori DNA amplification products from plaque, saliva, and/or gastric fluid samples. Negative bacterial cultures for cats for which there was demonstrable PCR amplification of H. pylori DNA may reflect the inability of in vitro culture techniques to isolate small numbers of H. pylori organisms, focal colonization at sites not cultured, or a failure of the antibiotics to successfully eradicate H. pylori from extragastric sites which allowed subsequent recolonization of the stomach after cessation of therapy. Alternatively, the treatment strategy may have induced in vivo viable but nonculturable coccoid forms of H. pylori. The H. pylori cat model should allow further studies to test these hypotheses as well as the efficacies of other combined therapeutic regimens. Also, because 100% of these cats were naturally infected with H.pylori, this model should prove useful in exploring mechanisms whereby human populations in underdeveloped countries, which have H. pylori infection rates approaching 100%, have a high rate of recurrence of H. pylori infection after use of prescribed antibiotic therapies that successfully eradicate H. pylori in individuals in developed countries.
Amoxicillin↗
Chronic proliferative hepatitis in A/JCr mice associated with persistent Helicobacter hepaticus infection: a model of helicobacter-induced carcinogenesis.
Helicobacter hepaticus causes hepatitis in selected strains of mice and in A/JCr mice is linked to liver cancer. To analyze whether H. hepaticus persists in specified ecological niches, to determine whether biomarkers of infection exist, and to analyze the influence of H. hepaticus on hepatocyte proliferation, a longitudinal study of H. hepaticus-infected A/JCr mice was undertaken. A/JCr mice were serially euthanatized from 3 through 18 months and surveyed by enzyme-linked immunosorbent assay; bacterial culture of liver, colon, and cecum; histology; electron microscopy; hepatocyte proliferation indices determined by using 5-bromo-2'-deoxyuridine; and measurement of the liver enzyme alanine aminotransferase. In infected animals throughout the 18-month study, H. hepaticus was consistently isolated from the lower bowel but only sporadically from the liver. By electron microscopy, H. hepaticus was noted infrequently and only in bile canaliculi. Infected mice, particularly males, showed chronic inflammation; oval cell, Kupffer cell, and Ito cell hyperplasia; hepatocytomegaly; and bile duct proliferation. The inflammatory and necrotizing lesion was progressive and involved the hepatic parenchyma, portal triads, and intralobular venules. Hepatic adenomas were noted only in male mice, whereas 5-bromo-2'-deoxyuridine proliferation indices were markedly increased in both sexes, but especially in males, compared to control A/J mice. Infected mice also developed sustained anti-H. hepaticus serum immunoglobulin G antibody responses and elevated alanine aminotransferase levels. H. hepaticus, which persists in the lower bowels and livers of A/JCr mice, is associated with a chronic proliferative hepatitis, and hepatomas in selected male mice indicate that this novel bacterium may cause an increased risk of hepatic cancer induction in susceptible strains of mice. This murine model should prove useful in dissecting the molecular events operable in the development of neoplasms induced by bacteria belonging to this expanding genera of pathogenic Helicobacter species.
Alanine Transaminase↗
Persistent hepatitis and enterocolitis in germfree mice infected with Helicobacter hepaticus.
Helicobacter hepaticus has been associated with naturally occurring hepatitis in certain inbred strains of mice, and in A/JCr mice it has been linked to the development of hepatic adenomas and adenocarcinomas. H. hepaticus was orally inoculated into 30 axenic, outbred female mice, and the mice were studied longitudinally to fulfill Koch's postulates and to ascertain the pathogenic potential of the organism under defined germfree conditions. Ten cage contact mice were also housed in the same germfree isolator to study transmission patterns, and 10 germfree mice were maintained in separate isolators as controls. Mice serially euthanized from 3 weeks through 24 months postinoculation (p.i.) were surveyed by culture and PCR for H. hepaticus in liver and intestinal tissues. Tissues were analyzed for histopathological changes, and sera were assayed for the presence of immunoglobulin G antibody to H. hepaticus and changes in the liver enzyme alanine aminotransferase. Inoculated mice and cage contact mice were persistently infected with H. hepaticus as identified by culture and PCR, in both the intestine and, less frequently, the liver, for the duration of the 2-year study. Animals developed persistent chronic hepatitis, and in some animals enterocolitis was noted. Hepatocellular carcinoma was diagnosed in one H. hepaticus-infected mouse. The level of H. hepaticus serum antibody was highest in experimentally infected mice at 12 to 18 months p.i.; this corresponded in general to the time interval when the highest levels of alanine aminotransferase were recorded. Although cage contact mice became persistently infected with H. hepaticus, lesions were less severe and the levels of serological biomarkers utilized in the study were lower. The H. hepaticus-infected mouse will provide an ideal model to study putative bacterial virulence determinants and how they interact with the host to induce chronic inflammation and tumorigenesis.
Animals↗
Helicobacter canis isolated from a dog liver with multifocal necrotizing hepatitis.
On the basis of biochemical, phenotypic, and 16S rRNA analysis, a novel gram-negative bacterium, isolated from normal and diarrheic dogs as well as humans with gastroenteritis, has been recently named Helicobacter canis. A 2-month-old female crossbred puppy was submitted to necropsy with a history of weakness and vomiting for several hours prior to death. The liver had multiple and slightly irregular yellowish foci up to 1.5 cm in diameter. Histologically, the liver parenchyma contained randomly distributed, occasionally coalescing hepatocellular necrosis, often accompanied by large numbers of mononuclear cells and neutrophils. Sections of liver stained by the Warthin-Starry silver impregnation technique revealed spiral- to curve-shaped bacteria predominantly located in bile canaliculi and occasionally in bile ducts. Aerobic culture of liver was negative, whereas small colonies were noted on Campylobacter selective media after 5 days of microaerobic incubation. The bacteria were gram negative and oxidase positive but catalase, urease, and indoxyl acetate negative; nitrate was not reduced to nitrite, and the organism did not hydrolyze hippurate. The bacteria were also resistant to 1.5% bile. Electron microscopy revealed spiral-shaped bacteria with bipolar sheathed flagella. By 16S rRNA analysis, the organism was determined to be H. canis. This is the first observation of H. canis in active hepatitis in a dog and correlates with recent findings of Helicobacter hepaticus- and Helicobacter bilis-related hepatic disease in mice. Further studies are clearly warranted to ascertain whether H. canis-associated hepatitis is more widespread in canines as well as a cause of previously classified idiopathic liver disease in humans.
Animals↗
Cystic urogenital anomalies in ferrets (Mustela putorius furo).
Single or multiple semispherical to bilobulated fluid-filled cystic structures of variable size were observed on the dorsal aspects of the urinary bladder of four male and two female ferrets (Mustela putorius furo). All ferrets had been neutered. On physical examination, the cysts were palpated as caudal abdominal masses. Three of the six ferrets presented with dysuria, and two ferrets had signs compatible with endocrine dysfunction. Adrenal cortical hyperplasia or neoplasia were observed in all of the five ferrets examined. Sex hormones assayed in one of the six ferrets revealed elevated levels of serum estrodiol. The posterior aspect of the cysts was located on and/or attached to the trigone or neck of the bladder, with variable intraluminal communication with the bladder and/or the urethra. The anterior aspect of the cysts projected dorsally or dorsocranially into the caudal abdomen. The cysts were thin walled and contained urinelike fluid (n = 5) or viscous yellow fluid (n = 1). Histologically, the cyst walls were composed of three layers, epithelium, muscle, and serosa, with fibrovascular stroma between layers. The epithelium consisted of simple to stratified transitional, columnar, or squamous epithelial cells. The muscular layer consisted of intermittent bundles and/or single to double layers of continuous to discontinuous smooth muscle. The serosal layer consisted of loose fibrous stroma covered by flattened mesothelial cells. The cystic anomalies in these ferrets were most likely derived from the urogenital glands/ducts or other remnants.
Adrenal Cortex Neoplasms↗
Intestinal plasmacytosis in rabbits: a histologic and ultrastructural study.
A retrospective study revealed intestinal plasmacytosis in 53 of 102 rabbits used in various experimental studies and as controls. The breeds affected included New Zealand white (n = 46), Dutch-belted (n = 6), and Watanabe (n = 1) rabbits. Sex predisposition was not found in any breed. The mean (+/-SD) ages were 3.1 +/- 1.4 years for New Zealand white rabbits, 1.3 +/- 1.1 for Dutch-belted rabbits, and 2 years for the Watanabe rabbit. The severity increased with animal age. The incidence was higher (P < 0.05) in rabbits used in antibody production and cholesterol studies. The lesions were characterized by multifocal to diffuse infiltration of well-differentiated plasma cells in the intestinal mucosa. Electron microscopic examination revealed typical plasma cell morphology of the infiltrating cells. Small intestine and cecum were the major sites affected. In severe cases, colon, rectum, trachea, esophagus, mesenteric lymph node, and spleen were also involved.
Aging↗
Clusters of lymphoma in ferrets.
Cluster outbreaks of lymphoma and leukemia have been associated with viral infections in many species including humans, cattle, and cats. This study describes epidemiological, clinical, and pathological features of cluster outbreaks of lymphoma in multiferret households and examines and compares the Aleutian disease virus (ADV) and feline leukemia virus (FeLV) status of cases, ferrets at risk, and controls. Three ferret groups with 21 cases of histologically diagnosed lymphoma (12.6% cumulative incidence) and their cohabitants (n = 35) were examined and compared with three control groups (n = 52) of cohabitating ferrets without lymphoma. A familial distribution was observed in one group but most cases were not consanguinous. Ferrets greater than 3 years of age developed chronic disease in two of the groups and 2-year-old adults had acute disease in the remaining group. Lymphocytosis, splenomegaly, and lymphadenopathy were prominent features. Histologically, predominantly small noncleaved cell and polymorphous lymphoid lesions were observed. All of the ferrets with lymphoma that were tested for ADV and FeLV using serology or PCR were negative. The rate of ADV antibody among cases or ferrets at risk was not significantly different from controls. None of the cluster ferrets were seropositive for FeLV p27 antigen using a monoclonal ELISA. Infection with a novel ferret virus is suspected, but an etiological agent has not yet been identified.
Aleutian Mink Disease Virus↗
Serous biliary cystadenoma in ferrets (Mustela putorius furo).
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Journal Article↗