PubMed Health⌕ Search

Biomedical subjects

R Bronson

Publications and source records attributed to R Bronson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Expression of the E2F-1/DP-1 transcription factor in murine development.

Because of its critical role in the control of cell proliferation and differentiation, we postulated that E2F-1 could have a role in murine development. To this end, the organ and developmental expression of the E2F-1 transcription factor was analyzed from mid-gestation to late-stage embryogenesis. We demonstrate that the mRNA levels for E2F-1 and its heterodimeric partner DP-1 reach maximal levels in the late embryonic and early postnatal period but decline in the later postnatal and adult periods. Additionally, using high resolution in situ hybridization, high expression of E2F-1 was observed in specific cells of individual tissues, suggesting that the role of E2F-1 may be more complex than previously indicated from cell culture studies. Furthermore, the unusual pattern of E2F-1 and DP-1 developmental expression may have an essential role in certain cells and tissues in the late embryonic and early postnatal period.

Animals↗
PubMed1995

Experimental autoimmune peripheral neuritis induced in BALB/c mice by myelin basic protein-specific T cell clones.

In vivo adoptive transfer of CD4+ T helper cell type 1 clones reactive with autologous myelin basic protein (MBP) may initiate an inflammatory demyelinating disease of the central nervous system called experimental autoimmune encephalomyelitis. Although MBP is also a component of peripheral nervous system (PNS) myelin, previous studies have failed to demonstrate inflammation in the PNS induced by MBP-reactive T cells. Here, we report on two MBP-specific T cell clones that preferentially initiate inflammatory and demyelinating peripheral neuritis when adoptively transferred to syngeneic recipients. The MBP epitope recognized by these clones spans the junction of exons 6 and 7 and, therefore, is present in the 21- and 18.5-kD but not the 14- and 17-kD MBP isoforms, in which exon 5 is spliced to exon 7. The data suggest that MBP may be processed and presented differently in the central nervous system and PNS, and they provide evidence for MBP as a potential target for autoimmune reactions in the PNS.

Amino Acid Sequence↗
PubMed1995

Life-span, T-cell responses, and incidence of lymphomas in congenic mice.

Survival, T-cell functions, and postmortem histopathology were studied in H-2 congenic strains of mice bearing H-2b, H-2k, and H-2d haplotypes. Males lived longer than females in all homozygous and heterozygous combinations except for H-2d homozygotes, which showed no differences between males and females. Association of heterozygosity with longer survival was observed only with H-2b/H-2b and H-2b/H-2d mice. Analysis using classification and regression trees (CART) showed that both males and females of H-2b homozygous and H-2k/H-2b mice had the shortest life-span of the strains studied. In histopathological analyses, lymphomas were noted to be more frequent in females, while hemangiosarcomas and hepatomas were more frequent in males. Lymphomas appeared earlier than hepatomas or hemangiosarcomas. The incidence of lymphomas was associated with the H-2 haplotype--e.g., H-2b homozygous mice had more lymphomas than did mice of the H-2d haplotype. More vigorous T-cell function was maintained with age (27 months) in H-2d, H-2b/H-2d, and H-2d/H-2k mice as compared with H-2b, H-2k, and H-2b/H-2k mice, which showed a decline of T-cell responses with age.

Animals↗
PubMed1995

Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques.

Adult macaques do not develop disease after infection with a nef deletion mutant of the simian immunodeficiency virus (SIV) and are protected against challenge with pathogenic virus. This finding led to the proposal to use nef-deleted viruses as live, attenuated vaccines to prevent human acquired immunodeficiency syndrome (AIDS). In contrast, neonatal macaques developed persistently high levels of viremia after oral exposure to and SIV nef, vpr, and negative regulatory element (NRE) deletion mutant. Severe hemolytic anemia, thrombocytopenia, and CD4+ T cell depletion were observed, indicating that neither nef nor vpr determine pathogenicity in neonates. Because such constructs have retained their pathogenic potential, they should not be used as candidate live, attenuated virus vaccines against human AIDS.

AIDS Vaccines↗
PubMed1995

Experimental autoimmune encephalomyelitis-resistant mice have highly encephalitogenic myelin basic protein (MBP)-specific T cell clones that recognize a MBP peptide with high affinity for MHC class II.

BALB/c mice are resistant to disease induction when experimental protocols that induce experimental autoimmune encephalomyelitis (EAE) in susceptible strains of animals are used. We have previously described a panel of myelin basic protein (MBP)-specific CD4+ T cell clones from BALB/c mice, two of which induce moderate EAE when transferred to syngeneic recipients. These clones are I-E(d) restricted and recognize residues 151-160 of mouse MBP. Here, we describe a series of 17 MBP-reactive T cell clones, which were derived from two BALB/c mice. All are I-A(d) restricted and recognize nested epitopes in peptide 59-76 of mouse MBP. Four different TCR V beta chains are used by this panel of clones; these include V beta 8.2 (10/17), V beta 8.1 (2/17), V beta 7 (3/17), and V beta 14 (2/17). Twelve of fourteen clones tested adoptively transferred severe demyelinating EAE to syngeneic recipients. Studies of relative binding affinities of MBP peptides to class II molecules I-A(d) and I-E(d) show that peptide 59-76 binds with extremely high affinity to I-A(d), whereas three peptides that contains residues 151-160 bind poorly to I-E(d). These results are consistent with a growing number of reports that show that high affinity binding to class II is required for autoantigenic stimulation. Despite encephalitogenicity of 59-76-reactive T cells, active immunization of BALB/c mice with peptide 59-76 in adjuvant failed to induce either clinical or histologic signs of EAE. The implications of these findings for mechanisms of genetically determined EAE resistance are discussed.

Amino Acid Sequence↗
PubMed1995

Prevention of tissue injury and postsurgical adhesions by precoating tissues with hyaluronic acid solutions.

The effectiveness of inhibiting serosal tissue damage and preventing surgical adhesions by precoating tissues with dilute solutions of hyaluronic acid (HA) was evaluated in a rat cecal abrasion model. This study was performed at three independent laboratories using the same protocol. Three hundred and seventy-five adult rats were divided into five treatment groups (125 animals at each study site): 0.1% HA, 0.25% HA, 0.4% HA, phosphate-buffered saline solution (PBS), and no solution. The abdominal cavity of each animal was precoated with 4 ml of test solution or no solution, prior to a controlled abrasion of the cecum. One week later, the animals were sacrificed and adhesions were scored on a 0-4 scale. The data were pooled because no statistical difference was found in the trends at the three study sites. The PBS precoating and no tissue precoating treatment groups had the same high incidence of cecal adhesions, which was significantly higher than the incidence of adhesions in the HA treatment groups. As the HA concentration in the precoating solution increased from 0% (PBS group) to 0.4% HA, the mean incidence of cecal adhesions decreased in a concentration-dependent manner from 1.6 +/- 0.11 to 0.7 +/- 0.09 (P < 0.001). The percentage of animals with no cecal adhesions increased from 11% in the PBS group to 50% in the 0.4% HA treatment group (P < 0.001). In a separate histological study employing 150 rats, HA solutions significantly inhibited serosal tissue damage and ameliorated the inflammatory response due to abrasion and desiccation compared to that with no coating or precoating with buffered saline. Together, these studies demonstrate that tissue precoating with dilute HA solutions reduces damage to serosal tissues during surgery and thereby limits formation of postsurgical adhesions.

Administration, Topical↗
PubMed1994

Physiological consequences of loss of plasminogen activator gene function in mice.

Indirect evidence suggests a crucial role for the fibrinolytic system and its physiological triggers, tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator, in many proteolytic processes. Inactivation of the t-PA gene impairs clot lysis and inactivation of the u-PA gene results in occasional fibrin deposition. Mice with combined t-PA and u-PA deficiency suffer extensive spontaneous fibrin deposition, with its associated effects on growth, fertility and survival.

Animals↗
PubMed1994

Chemoprevention of retroviral infection: success is determined by virus inoculum strength and cellular immunity.

We demonstrated earlier that post-exposure prophylaxis with 3'-azido-3'-deoxythymidine (AZT, zidovudine) or with AZT + interferon-alpha (IFN-alpha) prevented viremia and disease in BALB/c mice inoculated with Rauscher murine leukemia virus (RLV). After the 20-day treatment course, most animals were resistant to rechallenge with live virus. Adoptive transfer of T cells from such resistant but not from normal mice into naive recipients provided full protection against virus challenge. From these experiments, we concluded that post-exposure chemoprophylaxis restricted virus replication and allowed the animals to form protective, long-lasting cellular immune responses. Here, the role for cellular immunity during antiviral chemoprophylaxis was tested by comparing treatment success in normal BALB/c mice and in their nude, athymic counterparts. Both were inoculated with equal doses of RLV (10(4) plaque-forming units, pfu). Single-agent AZT or combination therapy with AZT + IFN-alpha, started before or after RLV inoculation, prevented viremia in all normal but not in most nude mice. A significant number of nude mice were completely protected by chemoprevention only when given a 10 times lower virus dose. When normal mice were injected with a 10 times higher virus dose (10(5) pfu), complete protection by chemoprevention was lost. These results demonstrate that the success of chemoprevention depends critically on the virus inoculum. The differential success of chemoprevention in normal and T-cell-deficient mice implies that effective cellular immunity plays an important role in protecting virus-exposed animals against viremia and disease.

Animals↗
PubMed1993

Tail chasing in a bull terrier.

A Bull Terrier that was continuously chasing its tail was examined clinically, electroencephalographically, and by computed tomography of the head. The dog was also given test treatments with an anticonvulsant (diazepam) and a pure opioid antagonist (naloxone). The dog appeared to be hysterical and dissociated from its surroundings. Electroencephalography revealed a seizure pattern that was most marked over the temporal lobe, and computed tomography revealed mild hydrocephalus. Diazepam effectively controlled tail chasing, whereas naloxone did not. The dog was discharged on anticonvulsant therapy but subsequently had to be euthanatized when aggression developed. Results of examination and treatment have led the investigators to propose a hereditary mechanism for tail chasing, perhaps related to zinc malabsorption.

Aggression↗
PubMed1993

Defect in entry and altered pathogenicity of a polyoma virus mutant blocked in VP2 myristylation.

We have examined effects of mutations of the minor capsid proteins VP2 and VP3 of polyoma virus. Infection of cells by mutants blocked in expression of either VP2 or VP3 by alterations of their initiator methionine codons led to the rapid selection of wild-type revertants. This reversion suggests a strong, if not absolute, requirement for both proteins in virus growth. A mutant virus, VP2*, in which alanine was substituted for glycine-2, expressed a nonmyristylated form of VP2 that was incorporated into virions. Studies of VP2* revealed a 15- to 20-fold lower specific infectivity and a delay in growth in both primary and established mouse cells compared to wild-type virus. Analysis of the growth delay indicated a defect in an early step of infection, at or prior to uncoating. Synthesis of viral DNA and VP1 was delayed by about 9 hr in mutant compared to that in wild-type infected cells. No evidence was obtained for an effect on either virus assembly (encapsidation) or stability of virions. Infection of mice by the VP2* mutant virus resulted in attenuated virus replication and tumor induction which were much more severely affected following intranasal inoculation than intraperitoneal inoculation.

3T3 Cells↗
PubMed1993

A retrovirus carrying the K-fgf oncogene induces diffuse meningeal tumors and soft-tissue fibrosarcomas.

The K-fgf/hst oncogene encodes a growth factor of the fibroblast growth factor (FGF) family and transforms cells through an autocrine mechanism which requires extracellular activation of its receptor(s). To identify the cell and tissue targets of K-fgf oncogenic potential in vivo, we constructed a recombinant retrovirus carrying the human K-fgf cDNA and injected it, together with helper Moloney murine leukemia virus, into immunocompetent as well as nude mice. The original construct was highly transforming in tissue culture but produced no detectable pathologies in vivo with the exception of a single fibrosarcoma which arose after a long latency. The virus produced by this tumor appears to have undergone a complex series of recombination events involving the helper Moloney murine leukemia virus. It encodes an Env/K-FGF fusion protein whose expression is under the control of a hybrid long terminal repeat. This virus (designated MFS, for meningeal fibrosarcoma) induces tumors in mice with high frequency and short latency. These neoplasms consist of aggressive fibrosarcomas of soft tissue as well as diffuse meningeal tumors originating from the dura mater that surround the whole central nervous system and cause severe hydrocephalus. The Env/K-FGF fusion protein expressed by the MFS virus has retained all of the biological properties of native K-FGF, including secretion, mitogenic activity, heparin binding, and neutralization by anti-K-FGF antibodies. These and other results indicate that the tumors induced by the MFS virus result from the oncogenic potential of K-FGF.

Animals↗
PubMed1993

Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization.

Homozygous plasminogen activator inhibitor-1 (PAI-1)-deficient (PAI-1-/-) mice were generated by homologous recombination in D3 embryonic stem cells. Deletion of the genomic sequences encompassing the transcription initiation site and the entire coding regions of murine PAI-1 was demonstrated by Southern blot analysis. A 3.0-kb PAI-1-specific mRNA was identified by Northern blot analysis in liver from PAI-1 wild type (PAI-1+/+) but not from PAI-1-/- mice. Plasma PAI-1 levels, measured 2-4 h after endotoxin (2.0 mg/kg) injection were 63 +/- 2 ng/ml, 30 +/- 10 ng/ml, and undetectable (< 2 ng/ml) in PAI-1+/+, heterozygous (PAI-1+/-) and PAI-1-/- mice, respectively (mean +/- SEM, n = 4-11). PAI-1-specific immunoreactivity was demonstrable in kidneys of PAI-1+/+ but not of PAI-1-/- mice. SDS-gel electrophoresis of plasma incubated with 125I-labeled recombinant human tissue-type plasminogen activator revealed an approximately 115,000-M(r) component with plasma from endotoxin-stimulated (0.5 mg/kg) PAI-1+/+ but not from PAI-1-/- mice, which could be precipitated with a polyclonal anti-PAI-1 antiserum. PAI-1-/- mice were viable, produced similar sizes of litters as PAI-1+/+ mice, and showed no apparent macroscopic or microscopic histological abnormalities.

Animals↗
PubMed1992

Polyoma tumorigenesis in mice: evidence for dominant resistance and dominant susceptibility genes of the host.

We have determined the tumor responses of nine inbred mouse strains and of two F1 hybrids following inoculation with polyoma virus. The results showed wide variations in the frequencies of mice developing tumors. Correlation with H-2 haplotype were evident. C3H/BiDa mice of H-2k type were fully susceptible, while C57BL/6 mice of H-2b type were completely resistant. DBA/2 and BALB/c mice, both H-2d, were of low susceptibility. Contributions of the major histocompatibility complex were demonstrated using pairs of H-2 congenic mice. Substitution of H-2k on either a BALB/c or a C57BL/10 background resulted in an increase in the frequencies and kinds of tumors induced. Susceptibilities of BALB and C57BL mice bearing the H-2k haplotype were still well below those of C3H/BiDa mice, however. Crosses of C3H/BiDa with BALB/c or BALB.K (H-2k) produced F1s that were of moderate and full susceptibility, respectively. These results indicate two distinct classes of host genes, one at the H-2 locus where different alleles confer varying degrees of resistance and the other a dominant susceptibility gene(s) carried in C3H/BiDa mice.

Animals↗
PubMed1992

Testicular origin of immunobead-reacting antigens in human sperm.

OBJECTIVE: To investigate, by means of immunobinding technique, the antigenic surface expression of human vasa efferentia sperm as compared with that of ejaculated sperm. DESIGN: Briefly, vasa efferentia sperm, retrieved microsurgically, and donors' ejaculated sperm (controls) were used. PATIENTS, PARTICIPANTS: Men with congenital absence of the vas deferens, undergoing sperm aspiration as part of their infertility treatment, and controls who were donors of our sperm bank were first assayed by direct immunobead test and, if found negative, were exposed to sera containing known high titers of antisperm antibodies and then retested by indirect immunobead test. RESULTS: The data showed no difference in binding titers and class of immunoglobulins between vasa efferentia and ejaculated sperm. CONCLUSIONS: These findings suggest that, in humans, sperm acquire those surface antigens commonly detected by immunobinding test within the testes before their transit through the epididymis.

Epididymis↗
PubMed1992

Traits that influence longevity in mice: a second look.

Analysis of genetic interactions in the F2 of an intercross of (C57BL/6 x DBA/2) F1J revealed influences of genetic factors on life span. Females lived longer than males. Dilute brown females died sooner than females of other colors. H-2b/H-2b males died sooner than H-2b/H-2d or H-2d/H-2d males, except that among dilute brown males those of typeH-2b/H-2d died sooner. Cluster analysis suggested that male and female genotypes each fall into two groups, with female dilute brown mice having shorter lives than other females, and male H-2b/H-2b mice except dilute brown and dilute brown H-2b/H-2d mice having shorter lives than other males. The association of heterozygosity with life span was clearer in females than in males, yet the longest-lived female genotype was homozygous H-2d/H-2d, of dominant Black phenotype at the Brown locus of chromosome 4, and homozygous dd at the Dilute locus of chromosome 9. The shortest-lived females were dilute brown H-2b/H-2b. The longest-lived and shortest-lived male genotypes were dilute brown H-2d/H-2d and dilute brown H-2b/H-2d, respectively. Although histological findings at postmortem differed between the sexes, there was no association of particular disorders with other genetic markers. The importance of H-2 in males was confirmed, but the allelic effects were perturbed, possibly by the absence of Sendai infection in this experiment. Overall our studies suggest that genetic influences on life span involve interactions between loci, and allelic interactions may change with viral infections or other environmental factors.

Animals↗
PubMed1991

Transplacental antiretroviral therapy with 9-(2-phosphonylmethoxyethyl)adenine is embryotoxic in transgenic mice.

Transgenic Mov-14 mice, which carry the provirus of Moloney murine leukemia virus (Mo-MuLV) in the germ line and begin to produce infectious virus on embryonic day 14, were used to evaluate the ability of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) to cross the placenta and protect embryos from viremia. We have used the Mov-14 model previously to demonstrate the antiviral efficacy and lack of teratogenicity of transplacental therapy with 3'-azido-3'-deoxythymidine (zidovudine, ZDV). PMEA was administered to pregnant females by daily intraperitoneal injection or by osmotic pump. In contrast to ZDV, PMEA was either noneffective in preventing viremia in the offspring or embryotoxic, depending on the dose. The specific toxic effects seen were resorption of pregnancy, low birth weight, and neonatal death. Histopathological analysis of neonatal mice exposed to PMEA showed severe lymphoid depletion of the thymus. We conclude that PMEA therapy is contraindicated for use during pregnancy.

Adenine↗
PubMed1991

Castanospermine vs. its 6-O-butanoyl analog: a comparison of toxicity and antiviral activity in vitro and in vivo.

Inhibitors of glycoprotein processing, such as castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine), have been shown previously to inhibit human immunodeficiency virus type 1 (HIV-1) with acceptable toxicity in cultured human cells. In prior experiments, we have tested the toxicity and antiviral efficacy of castanospermine in mice infected with the Rauscher murine leukemia virus (RLV). When compared with 3'-azido-3'-deoxythymidine (AZT, zidovudine), castanospermine was less effective and more toxic. Since the 6-O-butanoyl analog of castanospermine was previously found to have a more favorable activity profile than the parent compound against HIV-1 in cultured cells, we compared the antiviral efficacy of both compounds in parallel in vitro and in vivo in the RLV system. Plaque formation in the XC assay was inhibited with a 50% inhibitory concentration (IC50) of 2.4 microM for the 6-O-butanoyl analog of castanospermine, as compared to 9 microM for castanospermine. For both compounds, concentrations resulting in significant cytotoxicity were about ten times higher. Both compounds significantly decreased HIV-1 env-induced syncytium formation in a novel in vitro assay. In RLV-exposed mice, the 6-O-butanoyl analog showed no advantage over the parent compound: both curves for toxicity as well as antiviral efficacy were super-imposable. We conclude that the 6-O-butanoyl analog of castanospermine as well as castanospermine itself are active antiviral agents in mice and that prolonged oral administration is tolerable. However, in comparison to AZT, their antiviral activity profiles are less favorable.

Alkaloids↗