Genetic determination of susceptibility and resistance in the pathogenesis of Candida albicans infection.
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Animals↗
Biomedical subjects
R B Ashman
Publications and source records attributed to R B Ashman.
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Strain-dependent differences in host response to Candida albicans infection in mice are related to organ susceptibility and infectious load.
After systemic infection with the yeast Candida albicans, inbred mice show substantial differences in mortality, organ colonization, and severity of tissue damage. To examine the relationships between these variables, which are not directly correlated with each other, fungal colonization of the kidneys and brain was enumerated in six inbred strains that exhibit different patterns of tissue damage and mortality. Mice lacking the fifth component of complement (C5) are highly susceptible to lethal challenge, and A/J and DBA/2 mice, both C5 deficient, showed the highest colony counts in the kidneys after challenge with 10(5) blastoconidia. In contrast, colony counts in the brain of all six strains were equivalent at this challenge dose. A/J and DBA/2 mice died after challenge with 3 x 10(5) blastoconidia, but other strains showed an increase in kidney colonization, and strain-dependent differences in clearance from the brain became evident. The data suggest that mortality in A/J and DBA/2 mice is related to an unusual susceptibility of the kidneys to colonization by C. albicans and that there may be tissue-specific differences in host protective mechanisms.
Animals↗
Effect of spinal construct stiffness on short segment fusion mass incorporation.
STUDY DESIGN: Three segment (L3-L5) pedicle screw constructs were implanted in caprine spines, and the resulting ankylosis evaluated mechanically and compared 12 weeks after surgery. OBJECTIVES: To determine if a construct of maximal stiffness could impair the biologic process of spinal arthrodesis by "stress-shielding." SUMMARY OF BACKGROUND DATA: Fusion mass stiffness is believed to be enhanced by increasing construct stiffness, although previous studies have used semirigid, nonconstrained constructs, which lose stiffness through cyclical loading. Device-related osteoporosis, reported to occur with stiff, constrained implants, may be more related to the presence of fusion induced by the implants rather than the implants themselves. METHODS: In 15 goats, L3-L5 segments were instrumented with pedicle screws, and four different diameters of rods (3.2 cm, 4.8 cm, 6.4 mm, and no rods) were implanted as longitudinal connections to vary the stiffness of the constructs. After 12 weeks, animals were killed and the segments were tested to determine their stiffness. RESULTS: In lateral bending, spines "fused" with rods (any size) were significantly stiffer (P = 0.03) than nonrodded spines. There was a trend toward stiffer segments with larger rods (4.8 cm or 6.4 mm) compared with 3.2 mm or no rods. There was a highly significant (P < 0.0001) increase in stiffness of all operated (rodded or nonrodded) segments compared with unoperated controls. CONCLUSIONS: The enhancement of segmental stiffness by stiffer constructs was confirmed, suggesting a beneficial effect on spinal arthrodesis by increasing stiffness. Stress shielding could not be shown.
Animals↗
Computer-assisted surgery planning for lower extremity deformity correction by the Ilizarov method.
Starting in 1952, Prof. Gavril Ilizarov, a Russian orthopedic surgeon, devised a complex method of long bone deformity correction using an external bone fixation system consisting of rings and wires. We have developed a computer-assisted surgery planning system to aid in correction using the Ilizarov method. The hardware for the system is composed of an ultrasonic digitizer as input device, an HI plotter as output device, a 386/486 personal computer with super VGA monitor, and a mouse interfacing between user and computer. The software includes two separate programs. The main program is a menu-driven two-dimensional graphics program, which divides the planning procedure into several major stages, including preoperative planning and postoperative verification. The second program uses the information generated from the first program to create an image of the ideal three-dimensional frame construction to give a general impression of the appearance of the constructed frame.
Computer Simulation↗
Rapid destruction of skeletal muscle fibers by mycelial growth forms of Candida albicans.
The process of tissue invasion by the yeast Candida albicans after subcutaneous inoculation into the footpad of mice has been examined by light and electron microscopy. The blastospores germinated within 2 hr after injection. Hyphal and, to a lesser extent, pseudohyphal elements were observed penetrating into the adjacent striated muscle fibers and the endothelial cells of capillaries and destroying the collagen bundles of the interstitium. Electron microscopy showed evidence of structural tissue degradation associated with the mycelial elements, particularly at the apical tip. This was presumably due to fungal enzymatic activity. By 3 hr after infection, polymorphonuclear leucocytes had engulfed both the extracellular and intracellular mycelia, and often there was structural evidence of mycelial degradation. The results provide morphological evidence that initial tissue damage following subcutaneous infection is caused by the mycelial growth form.
Animals↗
Relations of mechanical properties to density and CT numbers in human bone.
Mechanical properties of cortical and cancellous bone from eight human subjects were determined using an ultrasonic transmission technique. Raw computerized tomography (CT) values obtained from scans of the bones in water were corrected to Hounsfield units. The correlations between CT numbers and mechanical property estimated from cortical bone were found to be low (r2 < 0.2), while these relationships for cancellous bone were found to be higher (r2 > 0.6). These results suggest that CT values may be useful in predicting mechanical properties only for cancellous bone. Poor correlations were found between modulus in the radial or circumferential direction and modulus in the superior-inferior direction for cortical bone, whereas good correlations were found between modulus in the anterior-posterior direction or medial-lateral direction and modulus in the S-I direction for cancellous bone. These results indicate that modulus in the radial or circumferential direction could not be predicted from modulus in the S-I direction for cortical bone, but could be predicted for cancellous bone. The predictive capabilities of linear and power models evaluated for cancellous bone alone were approximately equal. However, the power function gives a better fit of data at the low and high density values. The specific relationships, depending on the types of bone, that predict elastic modulus from density and CT numbers were suggested for human cortical and cancellous bone. These specific correlations may help a number of researchers develop more accurate models; however, these hypotheses should be proven by further study.
Aged↗
Cytokine mRNA in brain tissue from mice that show strain-dependent differences in the severity of lesions induced by systemic infection with Candida albicans yeast.
BALB/c and CBA/CaH mice show discrete, genetically determined patterns of tissue responses to infection with the yeast Candida albicans. By use of a semiquantitative reverse transcriptase-polymerase chain reaction, interferon (IFN)-gamma, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha were readily demonstrated in brain tissue on days 1, 3, and 5 after infection and were present in higher concentrations in CBA/CaH than in BALB/c mice. IL-2 and -4 were detected in both strains but at different time points. Both the fungus burden and the severity of the tissue damage become established before mRNA concentrations of the cytokines increase in the lesions, and the rate of clearance of the yeast is similar in both mouse strains. The data indicate that the deterministic model, which correlates Th1 and Th2 cytokines with resistance and susceptibility, respectively, is inadequate to account for the patterns of cytokine production that develop in the infected brain after sublethal challenge.
Animals↗
Production and function of cytokines in natural and acquired immunity to Candida albicans infection.
Host resistance against infections caused by the yeast Candida albicans is mediated predominantly by polymorphonuclear leukocytes and macrophages. Antigens of Candida stimulate lymphocyte proliferation and cytokine synthesis, and in both humans and mice, these cytokines enhance the candidacidal functions of the phagocytic cells. In systemic candidiasis in mice, cytokine production has been found to be a function of the CD4+ T helper (Th) cells. The Th1 subset of these cells, characterized by the production of gamma interferon and interleukin-2, is associated with macrophage activation and enhanced resistance against reinfection, whereas the Th2 subset, which produces interleukins-4, -6, and -10, is linked to the development of chronic disease. However, other models have generated divergent data. Mucosal infection generally elicits Th1-type cytokine responses and protection from systemic challenge, and identification of cytokine mRNA present in infected tissues of mice that develop mild or severe lesions does not show pure Th1- or Th2-type responses. Furthermore, antigens of C. albicans, mannan in particular, can induce suppressor cells that modulate both specific and nonspecific cellular and humoral immune responses, and there is an emerging body of evidence that molecular mimicry may affect the efficiency of anti-Candida responses within defined genetic contexts.
Animals↗
Association of a complement allotype (C3F) with acute inflammatory responses to Candida albicans infection.
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Candidiasis, Vulvovaginal↗
A comparison of reflection and transmission ultrasonic techniques for measurement of cancellous bone elasticity.
A reflection ultrasonic technique, which offers several advantages over transmission ultrasonic techniques, has been described for elastic property measurement of bone. Ultrasonic velocities from specimens of cancellous bone were compared using a reflection ultrasound technique and the more traditional transmission ultrasonic technique. The two techniques were found to yield velocities which were reasonably well correlated (r2 = 0.74). However, a statistical difference was found between the line of identity and the regression between transmission and reflection velocities (due to an offset in the intercept). In spite of differences in intercept between velocities measured by the two techniques, significant correlation was found between the two methods, suggesting that the reflection technique can measure wave velocities meaningful to bone elasticity.
Animals↗
Ultrasonically determined elasticity and cortical density in canine femora after hip arthroplasty.
Effects of canine hip replacement (with a porous-coated femoral component) on the material properties of surrounding cortical bone were evaluated. The hypotheses were: (1) after four months of implantation, mechanical properties of the cortex would change, and (2) a collared implant would be associated with smaller changes than a collarless design. Unilateral total hip arthroplasty was performed in 15 mixed-breed dogs. Nine received a collared and six received a collarless femoral component. Four months after implantation, longitudinal ultrasonic wave propagation velocities and bone mineral densities (from dual energy X-ray absorptiometry) were measured in harvested femora and used to calculate the axial elastic constitutive coefficients for the cortex surrounding the implants. Results showed no difference in bone elasticity or bone density between collared and collarless designs. Significant velocity decreases from control values (p < 0.0001) were noted in all implanted femora at four months. Bone mineral densities also displayed decreased values after four months of implantation (p < 0.0145). Elastic coefficients were consistently less after four months of implantation when compared to control values (p < 0.0001). This alteration in material properties would affect load transfer into the implanted femur via the increased disparity between implant and bone stiffnesses regardless of the component design. Significant differences in the elastic coefficients between implanted and control femora support hypothesis 1. However, no group differences were found between collared and collarless implantations; thus, the study does not support hypothesis 2.
Alloys↗