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PubMed1986

Genetic basis for a mouse model of Down syndrome.

The Trisomy 16 (Ts16) mouse has been proposed as a model for Down Syndrome (DS) in humans, based on genetic homology between mouse chromosome 16 (MMU 16) and human chromosome 21 (HSA 21). Translocations of HSA 21 resulting in trisomy for only a portion of the genetic information contained on this chromosome can result in a DS phenotype. Thus, these translocations help to define a "DS region" of the chromosome. A number of genes from this DS region of HSA 21 have been mapped to MMU 16. Techniques for localizing genes on chromosomes have been used to identify the portion of MMU 16 which corresponds to the DS region of HSA 21. This region appears to be highly conserved between mouse and human, providing further support for a mouse model of DS.

Animals↗

PubMed1987

Comparison of detection procedures for Chlamydia trachomatis, including enzyme immunoassays, in a mouse model of genital infection.

Two chlamydial enzyme immunoassays, Chlamydiazyme and IDEIA, were evaluated in a mouse model of chlamydial genital-tract infection. The Chlamydiazyme assay and the IDEIA were assessed on specimens from 10 and 11 mice, respectively. The animals were infected with Chlamydia trachomatis, strain SA2f, and the results obtained by these methods on vaginal specimens taken on 4 or 5 occasions during 41-42 days were compared with those obtained in cell culture and to a less extent by the MicroTrak direct immunofluorescence test. In comparison with culture, the Chlamydiazyme assay had a sensitivity of 62% and a specificity of 92%; IDEIA had a sensitivity of 76% and a specificity of 94%. These assays sometimes did not detect chlamydiae in specimens taken immediately before specimens which proved positive by culture and the immunoassays were less sensitive if swabs were taken after those for culture. The IDEIA also failed to detect chlamydiae in the late stage of the murine infection when chlamydial elementary bodies were seen by immunofluorescence. The implications of the observations for investigations in the human field as well as for further studies in the mouse are discussed.

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PubMed1980

The nude mouse model for human retinoblastoma: a system for evaluation of retinoblastoma therapy.

We have critically examined the nude mouse model for human retinoblastoma to determine whether or not characteristics found in the parent tumor are retained in the mouse. We have demonstrated that most tumors grown in the anterior chamber of the nude mouse maintain a similar karyotype, show the same degree of differentiation and develop an adequate tumor blood supply when compared to the primary tumor from which they were obtained. Because of these findings, we suggest that this model may be particularly useful for evaluating new methods or combinations of treatment for human retinoblastoma.

Animals↗

PubMed1995

Calculated and TLD-based absorbed dose estimates for I-131-labeled 3F8 monoclonal antibody in a human neuroblastoma xenograft nude mouse model.

Preclinical evaluation of the therapeutic potential of radiolabeled antibodies is commonly performed in a xenografted nude mouse model. To assess therapeutic efficacy it is important to estimate the absorbed dose to the tumor and normal tissues of the nude mouse. The current study was designed to accurately measure radiation does to human neuroblastoma xenografts and normal organs in nude mice treated with I-131-labeled 3F8 monoclonal antibody (MoAb) against disialoganglioside GD2 antigen. Absorbed dose estimates were obtained using two different approaches: (1) measurement with teflon-imbedded CaSO4:Dy mini-thermoluminescent dosimeters (TLDs) and (2) calculations using mouse S-factors. The calculated total dose to tumor one week after i.v. injection of the 50 microCi I-131-3F8 MoAb was 604 cGy. The corresponding decay corrected and not corrected TLD measurements were 109 +/- 9 and 48.7 +/- 3.4 cGy respectively. The calculated to TLD-derived dose ratios for tumor ranged from 6.1 at 24 h to 5.5 at 1 week. The light output fading rate was found to depend upon the tissue type within which the TLDs were implanted. The decay rate in tumor, muscle, subcutaneous tissue and in vitro, were 9.5, 5.0, 3.7 and 0.67% per day, respectively. We have demonstrated that the type of tissue in which the TLD was implanted strongly influenced the in vivo decay of light output. Even with decay correction, a significant discrepancy was observed between MIRD-based calculated and CaSO4:Dy mini-TLD measured absorbed doses. Batch dependence, pH of the tumor or other variables associated with TLDs which are not as yet well known may account for this discrepancy.

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PubMed1994

Sertoli cells in testes containing or lacking germ cells: a comparative study of paracrine effects using the W (c-kit) gene mutant mouse model.

BACKGROUND: Paracrine effects of germ cells on Sertoli cell structure were examined in a mouse model with the W locus (dominant white spotting) mutation in which animals with the W/Wv genotype (referred to as mutants) lack virtually all germ cells. RESULTS: Morphometric determination of Sertoli cell parameters in mutant and control (+/+) animals showed that although the testes of mutant animals were about eight times smaller than controls, the numbers of Sertoli cells in the two groups did not differ. Sertoli cell volume, Sertoli cell cytoplasmic and nuclear volumes, and Sertoli cell surface area in mutant animals were significantly smaller than in control animals. Organelle volumes and surface areas, expressed per cell, did not differ significantly in the two groups with one exception: the volume and surface area of smooth endoplasmic reticulum was significantly reduced in mutant animals. Plasma testosterone levels and tissue testosterone levels/testis were normal, indicating that the effects observed in the mutant animal were not a consequence of androgen insufficiency. Plasma FSH was elevated, probably as a consequence of germ cell depletion, and was thought not to affect Sertoli cell parameters observed. CONCLUSIONS: The data suggest that paracrine interactions with germ cells do affect Sertoli cells by modifying the amount of smooth endoplasmic reticulum. These data focus attention on the function of this abundant Sertoli cell organelle in promoting spermatogenesis.

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PubMed1985

Qualitative and quantitative analysis of muscarinic acetylcholine receptors in the piebald lethal mouse model of Hirschsprung's disease.

Cholinergic innervation in the aganglionic bowel of the piebald lethal mouse model of Hirschsprung's disease was investigated by analysis of muscarinic acetylcholine receptors before and after administration of hexamethonium. After hexamethonium administration in the normal rectum, the maximum specific binding (Bmax) of [3H]quinuclidinyl benzilate increased from 196.6 to 346.2 fmol/mg protein without affecting the dissociation constant. This increase of muscarinic acetylcholine receptors was associated with a decrease in the 50% effective dose (ED50) of contractile response to oxotremorine from 3.8 X 10(-7) M to 6.5 X 10(-8) M. In the aganglionic rectum, hexamethonium administration did not change the Bmax (166.4 fmol/mg protein) or dissociation constant value. The ED50 of contractile response to acetylcholine and oxotremorine (4.3 X 10(-8) M, 6.5 X 10(-8) M) was lower than that in the normal rectum (1.9 X 10(-7) M, 2.0 X 10(-7) M), but it was not changed by hexamethonium. It is concluded that cholinergic innervation is congenitally absent in the aganglionic rectum in piebald lethal mice.

Acetylcholine↗

PubMed1988

A mouse model for the study of blood-brain barrier permeability.

This article describes a C57BL/6 mouse model for the investigation of blood-brain barrier (BBB) alteration. Osmotic modification of BBB was achieved by infusion of 1.6 M arabinose solution into the internal carotid artery with or without occlusion of the external carotid artery. BBB alteration was measured by infusing 2% Evans blue dye. Only 1.6 M arabinose-treated animals but not 0.9% NaCl controls displayed prominent ipsilateral staining of frontal and temporal lobes. Light blue staining occurred in animals sacrificed within 10 min after injection. Prominent staining occurred in animals sacrificed 1-6 hours later. Identically treated animals were maintained for up to 6 months without signs of systemic or neurological dysfunction. This model may permit study of the effects of biological response modifiers (BRMs) upon the central nervous system (CNS) in healthy and diseased mice.

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PubMed1990

The sequence of changes in liver and brain in the influenza B virus mouse model of Reye's syndrome.

The time course of morphologic changes in the influenza B mouse model of Reye's syndrome is described and compared to the clinical, virologic, and biochemical changes. Following an intravenous inoculation of a lethal dose of an egg adapted strain of influenza B/Lee/40 virus, mice first showed clinical signs of lethargy and ruffled fur at 12 hours (h) post inoculation (pi). The earliest morphologic changes in the liver occurred at 12 h pi, and consisted of a slight increase in fat and loss of glycogen in hepatocytes. Over the next 36 h, the accumulation of microvesicular fat increased, and mitochondrial abnormalities such as pleomorphism and loss of dense bodies developed. There was no increase in peroxisomes. In the brain, focal cerebral edema was detected as early at 6-12 h pi. The edema, manifested as swelling of astrocytic foot processes, increased in severity with time. Endothelial cells were not abnormal. Myelin sheath splitting rarely was observed. Since changes occurred simultaneously in the liver and in the brain, we suggest that influenza B virus caused a simultaneous primary insult to both organs.

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PubMed2026

Progressive HNF1A-MODY pathophysiology revealed by a translational mouse model.

HNF1A-MODY, the most common monogenic diabetes, exhibits progressive β cell dysfunction, but existing mouse models fail to recapitulate human disease progression, limiting understanding of pathogenic mechanisms. We developed mice with heterozygous deletion of the Hnf1a transactivation domain (Hnf1a+/Δe4-10) to model human HNF1A haploinsufficiency, conducted cross-sectional metabolic characterization, and validated our findings in HNF1A-deficient human islets. Unlike previous models, Hnf1a+/Δe4-10 mice successfully recapitulated temporal HNF1A-MODY progression. Male mice developed sequential pathophysiology: early insulin resistance in young adults (7 weeks), followed by testosterone deficiency and fasting hyperglycemia in adult mice (10 weeks). Glucose intolerance emerged in middle-aged mice (30 weeks), progressing to multi-organ dysfunction in aged mice (44-70 weeks), characterized by elevated hepatic gluconeogenesis, impaired renal glucose handling, and hepatic steatosis/fibrosis. This dual pathophysiology involving β cell dysfunction and peripheral insulin resistance was associated with dysregulated hormone secretion from both α and β cells in aged mice (40-70 weeks). Human islet studies with HNF1A knockdown confirmed translational relevance, demonstrating reduced SGLT2 protein expression and inappropriate glucagon and insulin secretion. This work established a physiologically relevant HNF1A-MODY model, identified early insulin resistance as a key mechanism triggering hormonal dysfunction, and revealed HNF1A's role in multi-organ pathophysiology beyond traditional β cell dysfunction.

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PubMed1990

The influenza B virus mouse model of Reye's syndrome: clinical, virologic and morphologic studies of the encephalopathy.

The influenza B virus mouse model of Reye's syndrome was studied to learn more about the encephalopathy in Reye's syndrome. One to 3 days after intravenous influenza B/Lee virus, Balb/c mice became lethargic, seized and lapsed into a fatal coma. Wide-spread cerebral edema without inflammation developed 1-3 days after virus inoculation. Swollen astrocytic foot processes containing increased glial fibrillary acidic protein were located around capillaries. Viral particles were not seen by electron microscopy and complete viral replication did not occur. Immunohistochemical studies demonstrated influenza B viral antigen within many endothelial cells but not within other brain cells. Qualitative (Evans blue dye) and quantitative (percent brain water and technetium -99 pertechnetate) studies of the blood-brain barrier demonstrated abnormalities. This model reproduced many clinical, virologic and pathologic features of the Reye's syndrome encephalopathy. In addition, a non-permissive viral infection of brain endothelial cells occurred which may be important in the pathogenesis of the mouse encephalopathy and may participate in the encephalopathy of Reye's syndrome.

Animals↗

PubMed1991

Comparison of the pathogenicity of three species of coagulase-negative Staphylococcus in a mouse model with and without a foreign body.

Staphylococcus schleiferi, Staphylococcus lugdunensis, and Staphylococcus epidermidis produce a high incidence of abscesses in a mouse model with an implanted foreign body. We investigated the significance of the foreign body in this process. Fourteen strains of S. schleiferi, S. epidermidis, and S. lugdunensis were tested in our model. A preadhered foreign body was implanted into one mouse group, followed by injection of a test strain. Another group received injection without implant. Abscesses were assessed at 7 days; foreign bodies and infected tissues were cultured. The percent of samples that developed abscesses or were culture positive was compared for each strain. Nearly all mice infected with S. schleiferi developed abscesses and were culture positive. The foreign body made no difference in abscess formation for three of four S. schleiferi but increased the incidence of both organism recovery and abscess for three of five S. epidermidis. The foreign body enhanced abscess formation for four of five S. lugdunensis, with all five strains yielding significantly more culture recovery. Although the pathogenicity of nine strains was increased by the foreign body, five strains yielded high abscess and culture recovery rates that were not enhanced by its presence.

Abscess↗

PubMed1990

New mouse models for chronic Cryptosporidium infection in immunodeficient hosts.

Cryptosporidium sp. causes fulminant diarrhea and chronic infection in immunocompromised, particularly human immunodeficiency virus-infected, persons. The lack of in vitro cultivation and a suitable animal model has limited development of effective treatment. We describe two new mouse models of chronic symptomatic cryptosporidiosis in adult athymic mice and in T-cell subset-depleted mice. A progressive infection, fatal within 4 months, occurred in most adult athymic mice; a few developed stable infections. Symptoms included dehydration, weight loss, intermittent diarrhea, and jaundice. Pathologic abnormalities and organisms localized in the intestine in stable infections but involved the hepatobiliary tree and pancreas in others. Lymphoid cells from histocompatible, Cryptosporidium sp.-immune mice cured infected nude mice. Identical infections occurred in neonatally infected BALB/c mice treated with anti-CD4 monoclonal antibodies alone or also with anti-CD8 monoclonal antibodies; the mice were cured when the monoclonal antibody treatments were stopped. These models will be useful in definition of the immune defects that permit chronic cryptosporidiosis to develop and in assessment of treatment modalities.

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PubMed1995

Effect of ibotenate on brain development: an excitotoxic mouse model of microgyria and posthypoxic-like lesions.

Ibotenate, a glutamatergic agonist, was injected in developing mouse neopallium. When injected at the time of completion of supragranular neuronal migration (P0) ibotenate induces complete neuronal depopulation of layers V-VI and an abnormal sulcation of the overlying supragranular layers. Injected after completion of migration (P5-P10) ibotenate produces severe neuronal loss in layers II, III, IV, V, and VI. After exposure to ibotenate between P0 and P5, surviving neurons have the ability to resume their migration, inducing an abnormal neocortical pattern. Periventricular white matter lesions are observed after ibotenate injection at P2-P10, with a peak of occurrence at P5. Both gray and white matter damage are prevented by DL-2-amino-7-phosphonoheptanoic acid, an N-methyl-D-aspartate receptor antagonist, but not by L (+)-2-amino-3-phosphonopropionic acid, a metabotropic glutamate receptor antagonist. The microtubule-associated type 2 protein, a dendritic marker, is absent in all ibotenate lesions, which reflects the developmental impairment of the dendritic phase. These staged lesions of the gray and white matter disclose a developmental sequence of excitotoxin-affected events starting with the selective and layered sensitivity of postmigratory neocortical neurons and continuing in the white matter with the astroglial maturation and the axonal growth. They faithfully mimic microgyrias, focal cortico-subcortical dysplasias, porencephalic cysts, and white matter damage observed in human perinatal hypoxic/ischemic lesions. This mouse model provides tools for investigating excitotoxic influences on neural development at the various stages and for identifying protective substances against excitotoxicity from hypoxic and from nonhypoxic origins.

2-Amino-5-phosphonovalerate↗

PubMed1995

Role of the Helicobacter pylori virulence factors vacuolating cytotoxin, CagA, and urease in a mouse model of disease.

The pathogenic role of Helicobacter pylori virulence factors has been studied with a mouse model of gastric disease. BALB/c mice were treated orally with different amounts of sonic extracts of cytotoxic H. pylori strains (NCTC 11637, 60190, 84-183, and 87A300 [CagA+/Tox+]). The pathological effects on histological sections of gastric mucosae were assessed and were compared with the effects of treatments with extracts from noncytotoxic strains (G21 and G50 [CagA-/Tox-]) and from strains that express either CagA alone (D931 [CagA+/Tox-]) or the cytotoxin alone (G104 [CagA-/Tox+]). The treatment with extracts from cytotoxic strains induced various epithelial lesions (vacuolation, erosions, and ulcerations), recruitment of inflammatory cells in the lamina propria, and a marked reduction of the mucin layer. Extracts of noncytotoxic strains induced mucin depletion but no other significant pathology. Crude extracts of strain D931, expressing CagA alone, caused only mild infiltration of inflammatory cells, whereas extracts of strain G104, expressing cytotoxin alone, induced extensive epithelial damage but little inflammatory reaction. Loss of the mucin layer was not associated with a cytotoxic phenotype, since this loss was observed in mice treated with crude extracts of all strains. The pathogenic roles of CagA, cytotoxin, and urease were further assessed by using extracts of mutant strains of H. pylori defective in the expression of each of these virulence factors. The results obtained suggest that (i) urease activity does not play a significant role in inducing the observed gastric damage, (ii) cytotoxin has an important role in the induction of gastric epithelial cell lesions but not in eliciting inflammation, and (iii) other components present in strains which carry the cagA gene, but distinct from CagA itself, are involved in eliciting the inflammatory response.

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PubMed1986

A 66-base pair insert bridges the deletion responsible for a mouse model of beta-thalassemia.

The breakpoints of the deletion responsible for the Hbb(th-1) mouse model of beta-thalassemia have been isolated. A 3709 (+/- 2)-base pair (bp) region, including the entire beta major globin gene and 2 kilobases of 5' flanking region, is deleted. A novel 66 (+/- 2)-bp sequence, ending in a stretch of 25 dA:dT base pairs, was found to bridge the deletion. A region of the normal murine genome, containing the first 43 bp of the deletion-associated insert (DAI), but lacking the 25-bp dA:dT sequence, was isolated. All normal mice tested contain this DAI-like element and several inbred strains contain an additional DAI-like element. The sequence spanning the Hbb(th-1) deletion may be a reverse transcript of this region.

Animals↗

PubMed1984

Gastric emptying and small intestinal transit in the piebald mouse model for Hirschsprung's disease.

Gastric emptying and small intestinal transit were investigated in the piebald mouse model for Hirschsprung's disease. These mice exhibited aganglionosis of the terminal segment of the large intestine. This condition was accompanied by fecal stasis and megacolon. Gastric emptying of saline or milk meals was slower in the mice with aganglionic or induced megacolon than in the normal mice, but the rate of emptying was faster than after administration of morphine (10 mg/kg). In the small intestine, the distribution of the radiolabeled marker and the advancing edge of the marker profile were abnormal in the mice with megacolon. There were small differences between the megacolonic and normal mice in the distance traversed by the advancing edge of the intraluminal profile of the marker. These results are evidence for disturbances of gastric and small intestinal motor function that occur in mice secondary to development of megacolon.

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PubMed1982

A quantitative analysis of leptomeric fibrils in an adriamycin/carnitine chronic mouse model.

A quantitative ultrastructural analysis of leptomeres in cardiac muscle was performed using an adriamycin/carnitine chronic mouse model. Five animals from each of the following four groups were sacrificed for evaluation by electron microscopy: the control group received saline injections only; the carnitine group received carnitine orally; the adriamycin group received a chronic dose of adriamycin (10 mg/kg over 4 weeks); the adriamycin/carnitine group received both the adriamycin and carnitine dosage regimens. The leptomeres were quantitated using a double-blind method. The total number of leptomeres were scored for 20 random low-power electron micrographs from each of 5 animals within each group. The adriamycin group contained 3 of the 4 lowest leptomere scores. The relationships between myofibrillar disruption (MD) and the number of leptomeres found in an intramyofibrillar location(IML) were then determined for each of the four groups using linear regression analysis. In the control group, increased MD was associated with a decrease in the number of IML. In the carnitine group, increased MD was associated with an increase in IML. In the adriamycin group, no significant change in the number of IML occurred with increasing levels of MD. The adriamycin/carnitine group was similar to the control group. It was concluded from this study that 1) a relationship exists between MD and the number of IML in normal murine cardiac muscle; 2) carnitine produces an inverse effect on this normal relationship; 3) adriamycin disturbs the normal relationship between IML and MD; and 4) the administration of carnitine to adriamycin-treated animals restored the normal relationship. The physiological significance of the leptomere to the cardiac cell is then discussed.

Animals↗

PubMed1985

Glycemic modulation of tumor tolerance in a mouse model of breast cancer.

Marked sensitivity of tumor tolerance to blood glucose level is demonstrated in a mouse model of human breast cancer. A theory is cited that explains the high association of hyperglycemia with malignancy, especially breast cancer, via glycemic modulation of cellular immunity. Three groups of BALB/C mice were injected with an aggressive mammary tumor and placed on three dietary regimens designed to produce three different glycemic levels. Mortalities 70 days after injection were 16 of 24 hyperglycemic mice, 8 of 24 normoglycemic, and 1 of 20 hypoglycemic (chi-square p less than .005). Taken together with other experiments and human data discussed briefly, this result suggests that glycemic modulation of tumor tolerance should be evaluated in human trials.

Animals↗