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Biomedical subjects

R B Ashman

Publications and source records attributed to R B Ashman.

At least 19 recordsLinked to original sources
PubMed2001

Irradiation-induced oral candidiasis in an experimental murine model.

The aim of this experiment was to establish a mouse model of irradiation-induced oral candidiasis and to explore the cellular populations and mechanisms by which the infection is cleared from the oral mucosa. BALB/c mice received irradiation to the head and neck equivalent to 800 Rad using a Cobalt 60 gamma source. Both irradiated and non-irradiated mice were infected orally with 1 x 10(8) Candida albicans yeasts. Compared with untreated controls, irradiated animals developed a more severe infection of longer duration, with hyphae penetrating the oral mucosa. Monoclonal antibody depletion of CD4+ but not CD8+ T cells from the systemic circulation prolonged the infection in irradiated mice, but not in controls. Supernatants of submandibular and superficial cervical lymph node cultures from irradiated animals demonstrated significantly higher titers of interleukin-12, but similar levels of interferon-gamma compared with controls. Screening for cytokine production by an RNase protection assay detected only macrophage migration inhibition factor in irradiated and non-irradiated oral tissues from day 8 onwards. The results of this study demonstrate a requirement for CD4+ T cells in the recovery from oral candidiasis induced by head and neck irradiation in mice, and are consistent with a role for Th1-type cytokines in host resistance.

Analysis of Variance↗
PubMed2001

Mechanical testing of a single rod versus a double rod in a long-segment animal model.

This study involved the mechanical testing of single-rod segmental hook fixation and double-rod segmental hook fixation in a long-segment animal model. The goals were first to compare the flexibility of a single-rod scoliosis construct with that of a double-rod construct when tested in torsion, and second, to determine the effect of not using instrumentation with every vertebral segment for the single rod. Another study found that the single-rod construct was as stiff in torsion as the standard double-rod construct in a model of 10 vertebral segments. The amount of neutral zone (NZ) rotation was tested in five calf spines using an MTS (Material Testing System) machine. Five constructs were tested and included 1) a single rod with hooks at every level except the apex; 2) a single rod with two fewer hooks; 3) a single rod with four fewer hooks; 4) a double-rod construct; and 5) no instrumentation. The amount of NZ rotation between vertebral segments was measured over 12, 10, 8, 6, 4, and 2 vertebral segments. An analysis of variance with all constructs showed that the instrumented spines had significantly less movement than did the uninstrumented spine. Statistical comparison using analysis of variance of constructs (constructs 1 to 4) showed that over 12 vertebral segments (T4-L3), all single-rod constructs (constructs 1 to 3) allowed more NZ rotation than did the standard double-rod construct. This testing indicated that over 12 vertebral segments the single rod allowed more NZ rotation than a double-rod construct.

Animals↗
PubMed2001

T cells augment monocyte and neutrophil function in host resistance against oropharyngeal candidiasis.

The purpose of this study was to identify the cell populations involved in recovery from oral infections with Candida albicans. Monoclonal antibodies specific for CD4+ cells, CD8+ cells, and polymorphonuclear leukocytes were used to deplete BALB/c and CBA/CaH mice of the relevant cell populations in systemic circulation. Monocytes were inactivated with the cytotoxic chemical carrageenan. Mice were infected with 10(8) C. albicans yeast cells and monitored for 21 days. Systemic depletion of CD4+ and CD8+ T lymphocytes alone did not increase the severity of oral infection compared to that of controls. Oral colonization persisted in animals treated with head and neck irradiation and depleted of CD4+ T cells, whereas infections in animals that received head and neck irradiation alone or irradiation and anti-CD8 antibody cleared the infection in a comparable fashion. The depletion of polymorphonuclear cells and the cytotoxic inactivation of mononuclear phagocytes significantly increased the severity of oral infection in both BALB/c and CBA/CaH mice. High levels of interleukin 12 (IL-12) and gamma interferon (IFN-gamma) were produced by lymphocytes from the draining lymph nodes of recovering animals, whereas IL-6, tumor necrosis factor alpha, and IFN-gamma were detected in the oral mucosae of both naïve and infected mice. The results indicate that recovery from oropharyngeal candidiasis in this model is dependent on CD4+-T-cell augmentation of monocyte and neutrophil functions exerted by Th1-type cytokines such as IL-12 and IFN-gamma.

Animals↗
PubMed2000

Cellular and cytokine correlates of mucosal protection in murine model of oral candidiasis.

Host protection against Candida albicans infection in a model of oral candidiasis involving infection-prone [DBA/2 (H-2(d))] and less infection-prone [BALB/c (H-2(d))] mouse strains was analyzed in terms of antibody and cellular responses, and in terms of cytokine patterns from regional lymph node cells. There was a selective expansion of gamma/delta(+) T-cell receptor cells, which correlated with the patterns of colonization in both mouse strains, with higher numbers of gamma/delta T cells detected in BALB/c mice. Antigen-induced T-cell proliferation was significantly higher in BALB/c mice than in DBA/2 mice. Higher levels of serum immunoglobulin G (IgG) and salivary IgA antibodies were detected in BALB/c mice than in DBA/2 mice, but only after the infection was cleared. The cervical lymph node cells from infected mice were assessed for interleukin-4 (IL-4), IL-12, and gamma interferon (IFN-gamma) mRNA gene expression by reverse transcription-PCR and protein production in the culture supernatants following restimulation in vitro. In BALB/c mice, an early increase in levels of IL-4, IFN-gamma, and IL-12 correlated with rapid elimination of C. albicans. In DBA/2 mice, where resolution of infection was delayed, IL-4 message expression was delayed and the IL-4 secretion level was lower. Neutralization of IL-4 by multiple injections of an anti-IL-4 monoclonal antibody in BALB/c mice resulted in increased carriage rate and delayed clearance of the yeasts. Collectively, the data suggest that the T-cell response to C. albicans in the regional lymph nodes which correlates best with rapid oral clearance of C. albicans is a balanced Th0 cytokine response involving early secretion of both IFN-gamma and IL-4.

Animals↗
PubMed1999

Complement-mediated regulation of Trichomonas vaginalis infection in mice.

Trichomonas vaginalis is a flagellated protozoan which causes trichomoniasis, a sexually transmitted disease of the human genitourinary tract. The importance of the alternative complement pathway in host defence against T. vaginalis was investigated in vitro. Kinetic studies utilising immunofixation following electrophoresis showed that both a strongly and weakly virulent strain of T. vaginalis activated murine serum C3. In vivo studies with congenic-resistant, C5-deficient, B10.D2/OSn- and C5-sufficient, B10.D2/nSn mice showed that the presence of C5 is a significant factor in the innate host resistance to primary infection with a strongly virulent, but not a weakly virulent trichomonad strain.

Abscess↗
PubMed1998

A gene (Carg1) that regulates tissue resistance to Candida albicans maps to chromosome 14 of the mouse.

Tissue susceptibility and resistance to infection with the yeast Candida albicans is genetically regulated. Analysis of the strain distribution pattern of the C. albicans resistance gene (Carg1) and additional gene and DNA segment markers in the AKXL recombinant inbred (RI) set showed that 13/15 RI strains were concordant for Carg1, Tcra and Rib1. Therefore, Carg1 is probably located within a 17 cM segment of chromosome 14, within approximately 4 cM of the other two genes.

Animals↗
PubMed1998

A second Candida albicans resistance gene (Carg2) regulates tissue damage, but not fungal clearance, in sub-lethal murine systemic infection.

The severity of systemic infection with the yeast Candida albicans has been shown to be under complex genetic control. C57/L mice carry an allele that is associated with an increase in tissue destruction when compared with C57Bl/6 mice; however, the gene affects only the severity of tissue lesions, and does not influence the magnitude of the fungal burden in either kidney or brain. Studies in [C57/LxC57Bl/6]F1 hybrid mice, and [C57/LxC57Bl/6]F1xC57/L backcross mice, demonstrated that the gene behaves as a simple Mendelian co-dominant.

Alleles↗
PubMed1998

Type 1 and type 2 cytokines: from basic science to fungal infections.

At the present time, it is clear that Th1 responses afford protection against the fungi; however, the development, maintenance and function of the protective immune responses are complex mechanisms and are influenced by multiple factors. The route of infection has been shown to affect initial cytokine production and, consequently, the induction of protective Th1 responses. The ability of different isolates of the same fungal agent to induce and sustain a protective response has also been emphasized. Protective immune responses have been shown to vary in genetically different mouse strains after infection. In addition, these protective responses, such as cellular influx and cytokine production, also vary within the same animal depending on the tissue infected. The functional dominance of certain cytokines over others in influencing development and maintenance of protective responses has been discussed. Certain cytokines may act differently in hosts lacking important components of their innate or immune repertoire. It is evident from these presentations that a more comprehensive understanding of the protective mechanisms against different fungal agents is emerging. However, there is still much to learn before cytokine modulatory therapy can be used effectively without risk in the human host.

Animals↗
PubMed1997

Evidence that two independent host genes influence the severity of tissue damage and susceptibility to acute pyelonephritis in murine systemic candidiasis.

Tissue damage in the kidney and brain after systemic infection with Candida albicans was examined in recombinant inbred strains (AKXL) derived from AKR and C57/L progenitors. Nine of the 15 strains showed mild (C57/L-like) tissue damage. Of the remainder, two strains developed lesions comparable to the AKR parental strain, whereas four exhibited a much more severe pattern of tissue damage. This was characterized by pronounced mycelial growth in the brain, and gross oedema of the kidney, with extensive fungal colonization and marked tissue destruction. The presence of the null allele of the haemolytic complement gene (Hc) may be necessary, but not sufficient, for the expression of the very severe lesions. The results were interpreted as reflecting the actions of two independent genes, which have been designated Carg1 and Carg2 (Candida albicans resistance genes 1 and 2).

Alleles↗
PubMed1997

Anatomical variation of human cancellous bone mechanical properties in vitro.

The aim of the study was to assess mechanical properties of human cancellous bone in vitro. Six hundred cubic specimens of cancellous bone were obtained from the tibia, femur, patella, lumbar spine and humerus of eight subjects. The elastic properties were assessed using an ultrasonic transmission technique developed and validated by Ashman (1). The results showed that differences exist between subjects significantly (p < 0.05) and that the mechanical properties vary along the length and the periphery (about a factor 3 to 5). Cancellous bone should be considered heterogeneous and as orthotropic materials exhibiting degrees of anisotropy varying from 2 to 4. Linear and power fit elationships for cancellous bone were found approximately equal. Powers vary from 1.3 to 1.7 for axial modulus versus density and 1.3 and 2.3 for strength versus density. Finally, these results suggest the use of appropriate mechanical properties upon the type of bone for finite element analysis.

Aged↗
PubMed1996

Intraosseous infusion of prostaglandin E2 prevents disuse-induced bone loss in the tibia.

We investigated whether intraosseous injection of prostaglandin E2 would preserve tibial bone mass in the skeletally unloaded limb of a large animal model. Skeletal unloading of one rear limb was produced by unilateral Achilles tenectomy in the goat. Prostaglandin E2 was injected at 0.5 or 1.0 mg (1 ml of volume) twice daily, beginning on day 7 and continuing for 10 days, through an implant that had been surgically placed in the proximal tibial metaphysis. Thirty-five days after surgery, the tibiae were harvested for measurement of static and dynamic bone parameters and mechanical characteristics using transmission ultrasound. Prostaglandin E2 produced a dose-dependent increase in the formation of woven new bone at all bone envelopes. The 1.0 mg dosage prevented and partially reversed the effects of skeletal unloading and added new bone (p < 0.05) compared with the unloaded tibiae. Because prostaglandin E2 increased both bone formation and resorption and the new bone produced was primarily woven bone, the material properties of the tibiae infused with prostaglandin E2 did not increase significantly during the study compared with the unloaded and weight-bearing tibiae.

Animals↗
PubMed1996

Relationship of the virulence of Trichomonas vaginalis and the major histocompatibility complex in murine trichomonad infection.

A biological assay based upon the induction of abscesses in mice injected subcutaneously with Trichomonas vaginalis was shown to be a valid method for comparing the virulence of two isolates of T. vaginalis cultured from two patients, one suffering from severe vaginitis and the other exhibiting only mild disease. The data showed excellent correlation between the physical dimensions of abscesses in mice injected with each trichomonad isolate and the severity of vaginitis produced in the women from whom the isolates were obtained. The assay employed in our study incorporated measurement of the mean abscess volumes from day 1 to day 6 post-inoculation with T. vaginalis. We found that the abscess assay was clearly superior to a murine intraperitoneal assay for virulence evaluation of trichomonad isolates. We then used the murine abscess assay to determine the susceptibility of different strains of mice to infection with a virulent T. vaginalis isolate so as to test whether the genetic constitution of the host would influence the pathogenesis of the disease. BALB/c (H-2d) mice were susceptible to infection with T. vaginalis, but both CBA/CaH (H-2k) and BALB/c-H-2k mice were shown to be resistant. The quantitation of abscess formation in these inbred and congeneic resistant mouse strains demonstrates that the severity of infection with T. vaginalis is governed by genes mapping within the major histocompatibility complex.

Abscess↗
PubMed1996

Effects of anisotropy and material axis registration on computed stress and strain distributions in the turkey ulna.

Finite element stress and strain distributions were studied parametrically for a curved long bone using several common material simplifications. A new technique is presented whereby local material axes conforming to local surface topology were automatically computed. Linearly elastic stress/strain solutions were evaluated as a function of the manner in which principal material directions are defined. The simplifications inherent in assumptions of local isotropy or globally registered transverse isotropy led to appreciably different solutions, particularly for some of the lesser-magnitude components of the strain tensor.

Algorithms↗
PubMed1996

Acute labyrinthitis associated with systemic Candida albicans infection in ageing mice.

The yeast Candida albicans is an important opportunistic pathogen that has been associated with disease of the inner ear. This study describes the histopathology of acute labyrinthitis caused by systemic infection with C. albicans in aging inbred mice. Within four days after infection, yeast and hyphal forms of C.albicans were found in the membranous labyrinth. The utricle and the adjacent parts of the ampullary regions of the semicircular canals were most severely affected, but damage was also seen in the scala media, the scala tympani, the saccule, and the scala vestibuli. In the utricle, the lining epithelium of the membranous labyrinth was disrupted, and the lining cells of the vestibular membrane showed foci in which the membrane was disrupted. The data suggest that age may represent a risk factor for fungal labyrinthitis.

Acute Disease↗
PubMed1996

Neutrophil depletion increases susceptibility to systemic and vaginal candidiasis in mice, and reveals differences between brain and kidney in mechanisms of host resistance.

Infections caused by the yeast Candida albicans represent an increasing threat to debilitated and immunosuppressed patients, and neutropenia is an important risk factor. Monoclonal antibody depletion of neutrophils in mice was used to study the role of these cells in host resistance. Ablation of neutrophils increased susceptibility to both systemic and vaginal challenge. The fungal burden in the kidney increased threefold on day 1, and 100-fold on day 4, and infection was associated with extensive tissue destruction. However, a striking feature of the disseminated disease in neutrophil-depleted animals was the altered pattern of organ involvement. The brain, which is one of the primary target organs in normal mice, was little affected. There was a threefold increase in the number of organisms recovered from the brains of neutrophil-depleted mice on day 4 after infection, but detectable abscesses were rare. In contrast, the heart, which in normal mice shows only minor lesions, developed severe tissue damage following neutrophil depletion. Mice deficient in C5 demonstrated both qualitative and quantitative increases in the severity of infection after neutrophil depletion when compared with C5-sufficient strains. The results are interpreted as reflecting organ-specific differences in the mechanisms of host resistance.

Abscess↗
PubMed1996

Early inflammatory responses to Candida albicans infection in inbred and complement-deficient mice.

Inflammatory responses that developed in the footpad during the first 48 h after inoculation of Candida albicans were compared in six genetically defined inbred strains of mice. Tissue responses consisted predominantly of accumulations of polymorphonuclear leucocytes, the magnitude of which was significantly less in mice lacking the fifth component of complement (C5). Despite this, there was no difference between C5-sufficient and C5-deficient mice in the total infectious burden, nor did depletion of complement by treatment with cobra venom factor cause any detectable reduction in the numbers of inflammatory cells in the area of the lesion. Ablation of granulocytes had no significant effect on the fungal burden over the period of the experiment. Immunisation provided some protection against tissue damage, but did not reduce the number of yeasts at the site of infection.

Animals↗