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Biomedical subjects

M H Beaman

Publications and source records attributed to M H Beaman.

At least 19 recordsLinked to original sources
PubMed2000

Distribution of parasite stages in tissues of Toxoplasma gondii infected SCID mice and human peripheral blood lymphocyte-transplanted SCID mice.

The establishment of Toxoplasma gondii infection in the tissues of SCID mice and SCID mice transplanted with human peripheral blood lymphocytes (PBL) was investigated. The presence of bradyzoites and tachyzoites was analysed in hu-PBL SCID mice using Southern blot of reverse transcriptase-polymerase chain reaction products for the expression of B1, BAG1 and SAG1 of T. gondii. BAG1 was present by week 1 in brain, lung, liver and spleen of some animals; by week 3, BAG1 was present in all animals and in all of these tissues. In contrast, SAG1 was rarely detected until week 2 (mainly in the lung and brain) and by week 3, some animals still did not have detectable SAG1 in brain, lung, liver and spleen. SAG1 expression was increased in the lungs of animals transplanted with human PBL compared to nontransplanted SCID mice. Human PBL engraftment was demonstrated, initially in uninfected mice, by the presence of human CD3+ T cells in the spleen (3.1 x 10(5) positive cells) and peritoneal cavity (3.4 x 10(5) cells) 4 weeks after transplantation. The final outcome of infection was not influenced by the presence of human PBL, with similar mortality in human PBL transplanted and nontransplanted mice. These studies provide a detailed analysis of the kinetics and distribution of both the cyst and tachyzoite stage of T. gondii. This system has been established to allow evaluation of therapies against T. gondii immunodeficient mice in the presence of human immune cells.

Animals↗
PubMed2000

Human peripheral blood lymphocyte severe combined immunodeficiency (hu-PBL SCID) models of toxoplasmosis.

Toxoplasmosis is a potentially fatal opportunistic infection of immunocompromised hosts. Improved animal models of toxoplasmosis are needed to more nearly approximate conditions that occur in immunocompromised humans. The development of models of toxoplasmosis using human peripheral blood lymphocytes (hu-PBL) transplanted into severe combined immunodeficiency (SCID) mice is described here. Transplantation of hu-PBL into SCID mice without prior conditioning of the mice resulted in detectable differences in quantitative histological scores of brain inflammation due to Toxoplasma gondii infection, but did not alter mortality when compared to SCID mouse controls. The lack of detectable differences in survival were due to inadequate engraftment of hu-PBL, as assessed by flow cytometry. Unconditioned hu-PBL SCID mice had low titre T. gondii-specific antibody detectable after infection. When pretransplantation conditioning with irradiation and antiasialo GM 1 (n-glucolyl neuraminic acid) antibody was used, prolonged hu-PBL engraftment was observed in SCID mice, which was associated with worsened histopathology and usually impaired survival when compared with SCID mouse controls. When pretransplantation conditioning with irradiation, antiasialo GM antibody and polyethylene glycol-conjugated IL-2 was used, prolonged hu-PBL engraftment was also documented, but this did not affect survival from T. gondii infection when compared with similarly conditioned SCID mouse controls. The latter conditioning protocol resulted in hu-PBL SCID mice producing high titre T. gondii-specific antibody after infection. Conditioned hu-PBL SCID mice had evidence of increased T. gondii-induced inflammatory scores when compared with conditioned SCID mice. These models show promise for the study of the pathogenesis of toxoplasmosis and conditioned hu-PBL SCID mice may have applications for the evaluation of novel therapies for toxoplasmosis in immunocompromised humans.

Acute Disease↗
PubMed1997

The hypothalamic-pituitary-adrenocortical axis in severe falciparum malaria: effects of cytokines.

Patients with malaria can have features of adrenal insufficiency. Because of the pathophysiological and clinical implications of an Addisonian state, the hypothalamic-pituitary-adrenocortical axis was assessed in nine Vietnamese adults with complicated malaria. A CRH test was performed on admission (in convalescence in five cases) and in six healthy controls. Basal plasma ACTH concentrations in the patients and controls were similar [median (range): 2.9 (0.2-9.7) vs. 3.5 (1.9-13.4) pmol/L, respectively; P > 0.1]. Serum cortisol levels were greater in the patients [882 (294-1682) vs. 190 (110-676) nmol/L; P < 0.01], but three (33%) had values within the control range. Basal serum corticosteroid-binding globulin concentrations were similar in patients and controls (P = 0.23). The post-CRH rise in plasma ACTH was attenuated in the patients [peak: 6.1 (0.9-23.2) vs. 14.5 (6.2-21.5) pmol/L in controls; P < 0.05]; basal and peak plasma ACTH correlated with plasma interleukin-6 in this group (rs > or = 0.60; P < or = 0.04). Serum cortisol responses to CRH were depressed in acute illness [peak 990 (394-1, 805) nmol/L or 10 (0-50%) above baseline vs. 500 (429-703) nmol/L or 160 (10-380%) in controls; P < 0.05]. The median estimated serum cortisol t1/2 was 4.6 h in the patients and 1.6 h in the controls. These data suggest that, relative to a normal stress response, primary and secondary adrenal insufficiency can occur in severe malaria but may be attenuated by increased circulating interleukin-6 concentrations and impaired cortisol metabolism. The benefits of stress-dose corticosteroid replacement are unknown but could be considered in hypoglycemic patients or those with a serum cortisol within or below the reference range.

Adrenocorticotropic Hormone↗
PubMed1997

Emerging infections in Australia.

Over the last 10 years, novel infectious agents including Equine Morbillivirus, Lyssavirus, Barmah Forest Virus, Rickettsia honei and two as-yet-unnamed bunyaviruses have been identified as causes of human disease in Australia. Previously described agents, such as Japanese B Encephalitis virus, Dengue virus, Ross River virus, Orientia tsutsugamushi, Rickettsia australis, Burkholderia pseudomallei, Mycobacterium ulcerans and Trichinella pseudospiralis, have increased their geographical distribution over the last 20 years. Widespread antibiotic use has also resulted in selection for, and dissemination (especially in hospitals) of, multiresistant bacteria such as multiple-resistant Staphylococcus aureus (MRSA), expanded-spectrum beta-lactamase (ESBL) producing gram-negative bacteria, penicillin-resistant pneumococci and vancomycin-resistant enterococci (VRE).

Australia↗
PubMed1994

Enhancement of intracellular replication of Toxoplasma gondii by IL-6. Interactions with IFN-gamma and TNF-alpha.

Toxoplasma gondii is a major pathogen of immunocompromised hosts, and one defense mechanism against the parasite is activation of macrophages (M phi) for toxoplasmacidal activity by IFN-gamma after triggering by TNF-alpha. IL-6, IFN-gamma, and TNF-alpha are cytokines involved in inflammatory responses and are induced by T. gondii infection. We studied the interaction of these three cytokines using an in vitro model of T. gondii infection. Pretreatment (but not post-treatment) of unelicited murine peritoneal M phi with IL-6 enhanced T. gondii replication in a dose-dependent manner. Pretreatment with IFN-gamma resulted in active killing of parasites whereas the addition of IL-6 to IFN-gamma pretreatment resulted in a reversal of IFN-gamma-mediated toxoplasmacidal activity. Combining TNF-alpha with IL-6 and IFN-gamma pretreatment resulted in restoration of toxoplasmacidal activity. Addition of a polyclonal anti-TNF-alpha Ab to IL-6 and IFN-gamma pretreatment resulted in enhancement in the IL-6-mediated impairment of IFN-gamma function. These data taken together suggest that IL-6 enhances intracellular replication of T. gondii and reverses IFN-gamma mediated activation of murine peritoneal M phi, and that certain of the interactions between these two cytokines may be at the level of TNF-alpha triggering.

Animals↗
PubMed1994

Protective reconstitution of the SCID mouse against reactivation of toxoplasmic encephalitis.

A SCID mouse model of toxoplasmic encephalitis (TE) is described. Immunologic reconstitution using splenocytes from Toxoplasma gondii-immune allogeneic or nonimmune syngeneic donors was not successful in preventing reactivation of TE in chronically infected SCID mice. Splenocytes from immune syngeneic donors successfully prevented reactivation. Flow cytometry of spleens of transplanted mice demonstrated only transient reconstitution with allogeneic cells, but syngeneic lymphocytes exhibited prolonged engraftment. Reconstitution with syngeneic cells allowed enhanced production of T. gondii-specific antibody. In vitro depletion of CD4+ and CD8+ lymphocytes from BALB/c splenocytes before transplantation into infected SCID mice resulted in survival inferior to that of fully reconstituted SCID mice. Depletion of CD4+ or CD8+ cells before transplantation did not result in mortality, but transfer of CD(4+)-depleted splenocytes resulted in histologic evidence of reactivation of TE, whereas transfer of CD(8+)-depleted cells did not. This model could be used for study of the pathogenesis of TE and applied to the evaluation of therapies for TE in immunocompromised hosts.

Animals↗
PubMed1993

Cytokine mRNA in the central nervous system of SCID mice infected with Toxoplasma gondii: importance of T-cell-independent regulation of resistance to T. gondii.

Levels of cytokine mRNA were studied in the central nervous system (CNS) of SCID mice infected with Toxoplasma gondii. This infection led to 100% mortality by day 23 postinfection. Inflammation was observed in the lungs on day 7 and in the heart, liver, and kidneys on days 14 and 18 of infection. In the CNS, necrotic, acellular lesions that contained numerous parasites, accompanied by a localized astrocyte activation, were evident on day 14. Polymerase chain reaction-assisted amplification of RNA revealed that, although transcripts for interleukin-1 alpha (IL-1 alpha) and IL-1 beta were present in the brains of uninfected mice, increased levels of these transcripts were detected on day 7 of infection. Transcripts for macrophage inflammatory protein 1 and transforming growth factor beta were also detected in brains of infected mice at this time point. On days 14 and 18, levels of these transcripts had increased and transcripts for IL-6, IL-10, gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were also detected. Transcripts for IL-2 or IL-4 were not detected at any of the time points. Detection of locally produced cytokine transcripts may reflect involvement of the cytokines in the immunopathogenesis of this infection or involvement in mediating antitoxoplasma activity. To assess the possible role of endogenous IFN-gamma, TNF-alpha, IL-10, IL-6, and GM-CSF, cytokine-neutralizing monoclonal antibodies were administered to infected SCID mice. Neutralization of IFN-gamma or TNF-alpha led to earlier mortality than that in controls. In contrast, treatment with antibody to IL-10 and IL-6 increased survival time. Treatment with anti-GM-CSF did not alter the time to death. These results indicate that TNF-alpha and IFN-gamma are both involved in T-cell-independent mechanisms of resistance to T. gondii in SCID mice and that IL-10 and IL-6 may downregulate the immune response to this pathogen.

Animals↗
PubMed1991

Relapse versus reinfection with Clostridium difficile.

Relapse of Clostridium difficile-associated diarrhoea occurs in 15-20% of patients; however, whether relapse is due to an endogenous source of the organism or reinfection from the environment remains unclear. Restriction enzyme analysis (REA) of chromosomal DNA was used to type multiple isolates from ten patients who had experienced apparent relapses. More than half the relapses were due to infection with a new strain of C. difficile. The remaining patients were infected with the same strain, but whether this strain was acquired from the environment or from endogenous sources could not be determined. Relapses with a different strain of C. difficile could occur if an individual harboured more than one strain in their gastrointestinal tract. To investigate this possibility ten other patients were assessed for carriage of multiple strains. Ten colonies from a primary culture plate from each patient were typed by REA and tested for their ability to produce cytotoxin. All isolates from the same patient were identical by both methods, indicating that multiple carriage of strains may be a rare event.

Adult↗