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Biomedical subjects

D G Brownstein

Publications and source records attributed to D G Brownstein.

At least 37 records · Page 2Linked to original sources
PubMed1992

Serial backcross analysis of genetic resistance to mousepox, using marker loci for Rmp-2 and Rmp-3.

At least three genes from C57BL/6 mice that mediate dominant resistance to lethal mousepox were isolated and transferred onto a susceptible DBA/2 background. Three [(C57BL/6 x DBA/2)F1 x DBA/2] male mice that survived infection were selected as founders on the basis of different complements of marker loci for two resistance genes, Rmp-2r (Hc1) and Rmp-3r (H-2Db). They were crossed with DBA/2 mice, male progeny were infected with ectromelia virus, and the cycle was repeated with surviving male progeny through seven backcross generations. Two founders carried a marker locus for Rmp-2r or Rmp-3r, and the third carried neither marker locus. Resistance pedigrees were analyzed for passage of marker loci. From the three founders, resistance was passaged through multiple generations, producing backcross lines with intermediate-male-resistance phenotypes (20% resistant). Females of backcross lines with intermediate male resistance had high resistance (> 50%). High-resistance backcross lines (40% male resistance) also developed from the founders that carried marker loci for Rmp-2r and Rmp-3r, and marker loci were passaged through all generations of high resistance but not intermediate-resistance lines. About one-third of all resistant mice in high-resistance lines sired by mice that carried marker loci for Rmp-2r and Rmp-3r did not carry the respective marker locus. In lines that carried Rmp-2r, this was apparently not the result of recombination between Rmp-2r and Hc1, because Rmp-2 was not in the predicted location on chromosome 2 and because mice that did not inherit Hc1 transmitted significantly less male resistance than Hc1-positive mice, although female resistance remained high. These results confirmed that C57BL/6 mice have redundant resistance mechanisms, two of which are controlled at least in part by Rmp-2r and Rmp-3r, and provided evidence for a fourth resistance gene, herein presumptively named Rmp-4, which protects females more than males and which may be epistatic to Rmp-2.

Animals↗
PubMed1992

The pathogenesis of infection with minute virus of mice depends on expression of the small nonstructural protein NS2 and on the genotype of the allotropic determinants VP1 and VP2.

Neonatal C3H/He mice were oronasally inoculated with similar doses of four genotypes of minute virus of mice (MVM). MVMp, a fibroblast-specific variant, caused an asymptomatic infection. MVM(1035), a chimera which had the allotropic determinant of virulent MVMi inserted onto an MVMp background, caused a lethal infection and renal papillary infarcts, the hallmark of MVMi infection. MVMi(NS2-1990), the virulent lymphocyte-specific variant mutated to eliminate NS2 synthesis, was infectious but caused an asymptomatic infection. Sequential virus titration, histology, in situ hybridization with a full-length MVMi genomic probe, and immunohistochemistry for viral capsid antigen were used to compare the pathogenesis of infection with the four MVM genotypes. Infectious virus was recovered from multiple organs of mice infected with MVMi, MVMp, and MVM(1035) but not from mice infected with MVMi(NS2-1990). MVMp titers were lower than MVMi titers in all organs except the intestine. MVM(1035) titers were higher than MVMi titers in all organs except the blood. MVMp was localized to connective tissue elements of the intestine, to cells in mesenteric lymph nodes, and rarely to cells in other organs. MVM(1035) was localized to multiple organs and shared the same target cells, endothelium, lymphoid cells, and hematopoietic cells, as MVMi. MVM(1035) also replicated in external germinal cells of the cerebellum and smooth muscle cells of the stomach and colon, which were not targets of MVMi or MVMp infection. MVMi(NS2-1990) replicated to a limited degree in some MVMi target organs.

Animals↗
PubMed1992

Endometrial venous aneurysms in three New Zealand white rabbits.

Hematuria in rabbits has been associated with uterine adenocarcinoma, uterine polyps, renal infarction, urolithiasis, cystitis, bladder polyps, and pyelonephritis. Three adult female New Zealand White rabbits (Oryctolagus cuniculus) developed apparent hematuria, as suggested by blood in their excreta pans. They had been immunized with antigen-adjuvant emulsions, but had uneventful clinical histories. Physical examination disclosed no abnormalities, and laboratory tests, including hematology, serum chemistries, urinalyses, urine cultures, ultrasonography, and intravenous pyelography disclosed mild anemia, hematuria, and proteinuria in two of the rabbits. Antibiotic therapy failed to alleviate clinical signs. Two rabbits were euthanized because of persistent urogenital bleeding and the third rabbit underwent exploratory laparotomy and ovariohysterectomy. Multiple endometrial venous aneurysms were present in the uteri of all rabbits and urogenital bleeding was attributed to episodic bleeding from these lesions. Varices and aneurysms of uterine subserosal and myometrial venous plexuses, but not of endometrial vessels in women have been reported. To our knowledge, endometrial venous aneurysms have not been reported in animals previously. Our findings indicate that the differential diagnoses for sporadic apparent hematuria in female rabbits should include endometrial aneurysms.

Aneurysm↗
PubMed1991

Chromosomal locations and gonadal dependence of genes that mediate resistance to ectromelia (mousepox) virus-induced mortality.

Four genetic loci were tested for linkage with loci that control genetic resistance to lethal ectromelia virus infection in mice. Three of the loci were selected because of concordance with genotypes assigned to recombinant inbred (RI) strains of mice derived from resistant C57BL/6 and susceptible DBA/2 (BXD) mice on the basis of their responses to challenge infection. Thirty-six of 167 male (C57BL/6 x DBA/2)F1 x DBA/2 backcross (BC) mice died (22%), of which 27 (75%) were homozygous for DBA/2 alleles at Hc and H-2D. Twenty-eight percent of sham-castrated and 6% of sham-ovariectomized BC mice were susceptible to lethal mousepox, whereas 50% of gonadectomized mice were susceptible. There was no linkage evident between Hc or H-2D and loci that controlled resistance to lethal ectromelia virus infection in 44 castrated BC mice. Mortality among female mice of BXD RI strains with susceptible or intermediate male phenotypes was strongly correlated (r = 0.834) with male mortality. Gonadectomized C57BL/6 mice were as resistant as intact mice to lethal ectromelia virus infection. These results indicate that two gonad-dependent genes on chromosomes 2 and 17 and one gonad-independent gene control resistance to mousepox virus infection, that males and females share gonad-dependent genes, and that the gonad-independent gene is fully protective.

Alleles↗
PubMed1991

Pathogenesis of infection with a virulent allotropic variant of minute virus of mice and regulation by host genotype.

Neonates of various inbred strains of mice expressed three susceptibility phenotypes in response to infection with the lymphocyte-specific variant of minute virus of mice (MVMi). MVMi caused asymptomatic infections in C57BL/6 (B6) mice, lethal infections with intestinal hemorrhage in DBA/2 mice, and lethal infections with renal papillary hemorrhage in BALB/c, SWR, SJL, CBA, and C3H (H) mice. Sequential virus titration, histology, in situ hybridization with a full-length MVMi genomic probe, and immunohistochemistry for viral capsid antigen were used to compare the pathogenesis of MVMi infection in B6 and H mice. Peak infectious virus titers in heart, lung, liver, spleen, kidney and intestine did not differ between strains but brains of B6 mice, unlike H mice, were refractory to infection. Lesions in H mice consisted of renal papillary infarcts and accelerated involution of hepatic erythropoietic foci. No lesions were seen in B6 mice. In situ hybridization and immunohistochemistry indicated that three cell types were primary targets of MVMi; endothelium, lymphocytes, and hepatic erythropoietic precursors. Renal papillary infarcts in H mice were associated with virus replication in endothelial nuclei of the vasa recta. In contrast to the parity of infectious virus titers between strains, fewer cells in target organs of B6 mice were labeled with the MVMi probe then were labeled in H mice and fewer cells expressed viral capsid antigen. These results indicate (a) that the allotropic variants of minute virus of mice may be useful tools to dissect molecular mechanisms of parvovirus virulence, (b) that the virulence of MVMi for neonatal mice does not reside in its lymphotropism, and (c) that genetic susceptibility to lethal MVMi infection may result from overproduction of noninfectious virus products.

Animals↗
PubMed1989

Evidence that NK cells and interferon are required for genetic resistance to lethal infection with ectromelia virus.

C 57 BL/6 mice developed resistance to lethal intravenous challenge with virulent (Moscow strain) ectromelia virus between 2 and 3 weeks of age. The fraction of C57 BL/6 mice in which virus was detected in spleen was significantly lower than for DBA/2 mice by day 3. Thereafter, C 57 BL/6 mice had significantly reduced virus titers in spleen compared with those of DBA/2 mice. Resistance was abrogated by treatment with anti-asialo GM1 gammaglobulin, which blocks NK cell activity, or with anti-interferon (IFN) alpha, beta. C 57 BL/6 mice carrying the bg/bg mutation, associated with a deficiency of NK cells, were highly susceptible to lethal infection as were athymic mice derived from a resistant genetic background. Virus titers in spleens of C 57 BL/6 mice treated with anti-asialo GM1 or anti-IFN alpha, beta were significantly higher 4 days after virus challenge than were titers in C 57 BL/6 mice treated with normal rabbit serum. The results strongly suggest that genetic resistance to lethal ectromelia virus infection requires non-specific host defenses such as NK cells and IFN alpha, beta that are activated during the first 3 to 4 days of infection.

Aging↗
PubMed1988

In vitro adenylate cyclase-stimulating activity predicts the occurrence of humoral hypercalcemia of malignancy in nude mice.

A number of factors have been proposed as potential mediators of the syndrome of humoral hypercalcemia of malignancy (HHM), but to date no firm cause-and-effect relationship has been established. We attempted to establish such a relationship by determining whether the presence or absence of adenylate cyclase-stimulating activity (ACSA) in the media of cultured tumor cells predicted the occurrence of the syndrome of HHM when these cell lines were grown in nude mice in vivo. Conditioned media from 35 human renal carcinoma cell lines were surveyed for ACSA in the PTH-sensitive rat osteosarcoma 17/2.8 cell assay. 12 lines were positive (mean, 13.7-fold stimulation, range, 3.0 to 44.0), and 23 lines were negative (mean, 1.2-fold stimulation, range, 0.9 to 1.5). We were successful in establishing five of the positive and six of the negative lines in three to five nude mice per line. Mice implanted with the positive lines uniformly became hypercalcemic (mean serum calcium, 15.8 mg/dl), whereas mice implanted with the negative lines uniformly remained normocalcemic (mean serum calcium, 9.5 mg/dl), in spite of comparable mean tumor size. Acid-urea tumor extracts from each of four hypercalcemic animals contained potent in vitro ACSA (mean, 15.9-fold stimulation), while 5/5 extracts from normocalcemic animals did not (mean, 1.4-fold stimulation). Our study demonstrates that in this model system in vitro ACSA is a reliable predictive marker for HHM in vivo. Whether the protein responsible for this activity is also the mediator of the bone resorption seen in HHM remains to be demonstrated.

Adenylyl Cyclases↗
PubMed1988

The effect of selected viruses on Corynebacterium kutscheri infection in rats.

The influence of selected viral pathogens on rats that were previously infected with Corynebacterium kutscheri was investigated. A series of three separate experiments were performed to test the effect of sialodacryoadenitis virus, Sendai virus and rat virus. In each experiment, weanling rats were divided into three groups (C. kutscheri-inoculated, virus-inoculated and C. kutscheri plus virus-inoculated). Two groups were inoculated oronasally with C. kutscheri to establish subclinical infections. Two weeks later, two groups were inoculated intranasally with virus. At 5 weeks, the prevalence of C. kutscheri recovery from oral cavity and submaxillary lymph node and the prevalence of overt pseudotuberculosis was compared between treatment groups. Seroconversion of rats to C. kutscheri was measured by microagglutination and viruses by indirect immunofluorescence assays. Infection of rats with sialodacryoadenitis virus, Sendai virus or rat virus had no discernable effect on C. kutscheri-infected rats.

Animals↗
PubMed1988

Respiratory disease and wasting in athymic mice infected with pneumonia virus of mice.

Although pneumonia virus of mice (PVM) is ubiquitous among rodent colonies in the United States, it has not been reported to cause clinically apparent disease in euthymic mice. However, PVM has been reported to cause respiratory disease and death in experimentally infected euthymic and athymic mice. A group of nu/nu mice, housed in quarantine in a Trexler-type isolator, had weight loss and dyspnea. Gross necropsy findings included cachexia and diffuse pulmonary edema or lobar consolidation. Histologically there was diffuse interstitial pneumonia. Electron microscopy revealed filamentous virions budding from plasma membranes, and immunohistochemical staining of lung tissue was positive for PVM antigen. PVM was isolated from affected lung tissue in BHK 21 cells and mouse antibody production tests resulted in seroconversion to PVM. Experimental inoculation of athymic mice with lung homogenate from spontaneously infected mice resulted in clinically apparent respiratory disease and histologic lung changes similar to those in naturally infected mice. Inoculation of athymic mice with infected BHK 21 cell culture fluid resulted in pneumonia which was qualitatively similar to, but less severe than, that observed in mice with spontaneous disease. These findings indicate that naturally occurring PVM infection in athymic mice may cause respiratory disease and wasting.

Animals↗
PubMed1987

Genetic determinants of lung virus titers and resistance to lethal Sendai virus pneumonia.

C 57 BL/6J mice are resistant to lethal Sendai virus pneumonia and have lower lung virus titers than susceptible DBA/2J mice. Linkage between these phenotypes was tested indirectly in segregant hybrids. Sas-1, B2m, and b on chromosomes 1, 2, and 4 were linked to significant (P less than .05) differences in virus-induced mortality; d on chromosome 9 was associated with a similar but smaller difference (.1 greater than P greater than .05). Mean lung virus titers were higher in F1 X DBA/2J mice that were homozygous for DBA alleles at B2m, b, and d than in heterozygotes. The difference in lung virus titers was larger between mice that were dihomozygous/diheterozygous for paired combinations; B2m-d (P less than .02), B2m-b (P less than .06), and b-d (P less than .05) and largest between mice that were trihomozygous/triheterozygous for B2m-b-d (P less than .001). The distribution of virus titers among 22 recombinant inbred strains derived from C 57 BL/6J and DBA/2J progenitors indicated 1) that the loci linked to B2m, b, and d are among at least 4 loci that regulate lung virus titers, 2) that Sas-1 may be linked to a fourth locus, 3) that the C 57 BL/6J genome contains at least one susceptibility locus, possibly within H-2, and 4) that some of these loci may be expressed through natural killer cell activity.

Animals↗
PubMed1987

Resistance/susceptibility to lethal Sendai virus infection genetically linked to a mucociliary transport polymorphism.

Linkage was tested between a mucociliary transport polymorphism and resistance/susceptibility to lethal Sendai virus infection in segregant hybrid mice of C57BL/6J and DBA/2J parents. The distribution of paired phenotypes for tracheal mucociliary transport rates and susceptibility to lethal Sendai virus infection in 171 F1 X DBA/2J mice showed strong interaction of the parental phenotypes.

Animals↗
PubMed1987

Tracheal mucociliary transport in laboratory mice: evidence for genetic polymorphism.

Mean tracheal transport velocities of inhaled 3 mu coumarin-bound monodisperse latex spheres, measured by epi-fluorescence through the intact trachea of anesthetized mice, were 2.29 +/- 0.52 mm/min for C57BL/6J, 0.40 +/- 0.42 mm/min for DBA/2J mice and 1.47 +/- 0.87 mm/min for (C57BL/6J X DBA/2J) F1 mice. A nonparametric analysis of the observed proportions of mice expressing parental phenotypes in second filial, two first backcross and one second backcross generations confirmed the polymorphism to be genetically determined and consistent with a single-locus mode of inheritance.

Animals↗
PubMed1987

Immunostimulation in mice infected with Sendai virus.

The effect of Sendai virus infection on the splenic primary plaque-forming cell (PFC) response to sheep RBC in 2 strains of mice, with contrasting susceptibility to Sendai viral pneumonia, was examined. Mice were given single inoculations of sheep RBC, which varied relative to time of inoculation with Sendai virus, PFC were counted 6 days later, and were compared with PFC responses from noninfected mice. The IgM- and IgG-PFC responses were augmented in resistant C57BL/6J mice 7 and 9 days after inoculation with Sendai virus (sheep RBC given 1 and 3 days after inoculation with Sendai virus, respectively) and in susceptible DBA/2J mice 7, 9, 10, and 13 days after inoculation with Sendai virus. Augmentation was restricted mainly to IgM-, IgG3-, and IgG2b-PFC. The number of splenic background antitrinitrophenyl sheep RBC PFC in mice of both strains was examined during the course of Sendai virus infection. Only a marginal increase in background PFC was seen in C57BL/6J mice on or after viral inoculation day 11 and no change was seen in DBA/2J mice. Serum of infected mice also was examined sequentially for alpha/beta interferon (IFN). Despite vigorous lung IFN production, infected mice rarely had detectable circulating IFN. Seemingly, Sendai virus infection can induce transient hyperresponsiveness to a nonviral antigen.

Animals↗
PubMed1986

Genetic resistance to lethal Sendai virus pneumonia: virus replication and interferon production in C57BL/6J and DBA/2J mice.

Resistant C57BL/6J and susceptible DBA/2J mice were exposed to aerosols of Sendai virus and killed at intervals to 12 days. Lungs were removed and assayed for infectious virus and interferon. Mean virus titers were 6 to 400 times higher in DBA/2J mice than in C57BL/6J mice 3 to 10 days after exposure. Mean interferon titers were 10 to 140 times higher in DBA/2J mice than in C57BL/6J mice 4 to 7 days after exposure. These results suggest that genetic resistance to the lethal effects of Sendai virus is expressed through control of viral replication within the first 72 hours of infection and that early expression of inherited resistance is not regulated by interferon.

Animals↗
PubMed1986

Spontaneous wasting disease in nude mice associated with Pneumocystis carinii infection.

Several cases of wasting disease and dyspnea occurred in outbred Crl: CDI(ICR) nu/nu mice obtained recently from a commercial supplier. Gross necropsy revealed pulmonary consolidation, and histologically there was alveolar-wall thickening and filling of alveoli with macrophages and honey-combed eosinophilic material. Electron microscopic examination of lung tissue confirmed infection with Pneumocystis carinii.

Animals↗
PubMed1985

Experimental Corynebacterium kutscheri infection in rats: bacteriology and serology.

In a preliminary study, hydrocortisone-treated rats developed pseudotuberculosis when challenged with 6.2 X 10(5) to 3.1 X 10(7) colony forming units of Corynebacterium kutscheri by intranasal, intragastric, or subcutaneous inoculation. Oronasal exposure was selected as a likely natural route to further study inapparent infection. In Study 1, 50 rats received 1.2 X 10(5) colony forming units and various tissues were cultured at intervals to 12 weeks post-inoculation. At each interval, C. kutscheri was regularly isolated from submaxillary lymph nodes, but isolation was sporadic from other sites. In Study 2, 17 out of 21 rats given 1.2 X 10(5) colony forming units and killed weekly for 6 weeks had 2.0 X 10(2) to 1.8 X 10(5) colony forming units of C. kutscheri in oral washes, and 16 rats had 2.0 X 10(2) to 1.0 X 10(5) colony forming units in submaxillary lymph nodes, Serum antibody to C. kutscheri using both microagglutination and indirect immunofluorescence was first detected in some rats by 2 weeks, and in all rats at subsequent intervals. There was a significant (P less than 0.001) positive correlation (r = 0.93) between serum antibody titers and the duration of infection.

Animals↗