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Biomedical subjects

David Abraham

Publications and source records attributed to David Abraham.

27 records · Page 2Linked to original sources
PubMed2002

Strongyloides stercoralis: high worm population density leads to autoinfection in the jird (Meriones unguiculatus).

At 28 days post-infection autoinfective third-stage larvae (L3a) of Strongyloides stercoralis occurred in jirds infected with 10,000 infective third-stage (L3i). Previously in the jird model of strongyloidiasis, autoinfection had been seen in immunologically immature or immunosuppressed jirds only. The heavily infected jirds described herein had a strong anti-L3i immune response at the same time the living L3a were found in their tissues. This was demonstrated by the rapid killing of L3i in subcutaneously implanted diffusion chambers. No decrease of intestinal motility was observed in these heavily infected jirds, indicating that an increased time for development was not the explanation for the presence of L3a. These larvae were found only in jirds when concomitantly a large number of first-stage larvae (L1) occurred in the intestines. We suggest that the development of L3a in the adult jird model is a rare event and thus, autoinfection occurs only when the intestinal population of L1 is very large, as was the case in the heavily infected jirds. Index Descriptors and Abbreviations. Nematode; Strongyloides stercoralis; Mongolian gerbil; Meriones unguiculatus; autoinfection; larval development; L3i, infective third-stage larva(e); L3i+, tissue migrating third-stage larva(e); L3a, autoinfective third-stage larva(e); L1, first-stage larva(e); PI, post-infection.

Animals↗
PubMed2002

Steroids in Duchenne muscular dystrophy: from clinical trials to genomic research.

Steroids represent the only pharmacological palliative treatment for Duchenne muscular dystrophy. However, they do have side effects and despite a large number of published studies showing their efficacy, they are still not universally used. This is largely due to the lack of functional outcome and quality of life measures in most of the published studies and suggests that further trials might be required to answer some of the still unclear aspects of their role. Another important aspect of steroid therapy in Duchenne dystrophy is that we do not know how they work in dystrophic muscle. We have initiated a collaborative study on gene profiling using microarray in steroid-treated mdx mice. cDNA microarray studies were performed to examine the levels of skeletal muscle gene expression in a pool of mdx mice treated with prednisolone for 1 and 6 weeks. Interesting preliminary data on untreated mdx mice suggest that the gene profiling of young (7 weeks) versus older (12 weeks) mice is very significantly different. Furthermore, a large number of genes showed significant changes in expression at the mRNA level on treatment with prednisolone. These included structural protein genes; signalling genes and genes involved in immune response. Hopefully, analysis of this pattern of steroid-induced gene expression will provide some insight into understanding how glucocorticoids improve strength in Duchenne dystrophy, and may help in developing more effective and less toxic therapeutic approaches.

Adrenal Cortex Hormones↗
PubMed2002

Towards a recombinant antigen vaccine against Onchocerca volvulus.

Various approaches to identify potential vaccine candidates against onchocerciasis resulted in the cloning of recombinant proteins, which confer protection in vaccinated mice. The development of an effective vaccine against onchocerciasis has been the focus of a research program supported by the Edna McConnell Clark Foundation from 1985 to 1999. The approaches used to clone potential protective antigens and the successful vaccination of animals with some of the antigens are summarized here.

Animals↗
PubMed2002

Immunity to Onchocerca spp. in animal hosts.

This review summarizes research using Onchocerca spp. in chimpanzees, cattle and mice to gain insight into the protective immune response to the filarial worm Onchocerca volvulus in humans. In addition, Acanthocheilonema viteae has been evaluated as a surrogate filarial worm for studying immunity to the infection. Immune mechanisms controlling these infections are described and initial success using recombinant antigen vaccines in these models is reviewed.

Animals↗
PubMed2002

The role of B cells in immunity against larval Strongyloides stercoralis in mice.

The objective of this study was to examine the role of B cells in primary and challenge infections of larval Strongyloides stercoralis in mice. Two strains of B-cell deficient mice were used in these studies, microMT mice that lack all B cells and Xid mice that lack B-1 cells. Primary immune responses in microMT mice were sufficient to eliminate all parasites within 1 week after infection. Immunized microMT and Xid mice, however, were unable to kill challenge parasites at 24 h post infection, the time that they were eliminated in immunized wild-type mice. This was despite having a significant increase in interleukin-5 secreting cells and high numbers of eosinophils in the microenvironment of the challenge larvae. In addition, immunized Xid mice did not generate parasite-specific immunoglobulin (Ig)M but did develop a weak IgG response compared to wild-type mice. These results demonstrate a dichotomy in the requirement of B cells in immunity to S. stercoralis. B cells are not required in the primary response, yet they are required in the secondary immune response. B-1 cells are required for the secondary immune response and their role appears to be the production of IgM and not as a source of immunoregulatory molecules.

Animals↗
PubMed2002

Onchocerca volvulus glycolytic enzyme fructose-1,6-bisphosphate aldolase as a target for a protective immune response in humans.

To identify potential vaccine candidates for the prevention of infection with the filarial nematode Onchocerca volvulus, we screened an O. volvulus L3 stage cDNA library with sera from putatively immune (PI) subjects, and a prominent immunogenic clone of 1,184 nucleotides was identified. It contained an open reading frame of 363 amino acids encoding the glycolytic enzyme fructose 1,6 bisphosphate aldolase (Ov-fba-1). Immunolocalization experiments demonstrated that the protein was most abundantly expressed in metabolically active tissues, including body wall muscle and the reproductive tract of adult female worms. Immunoelectron microscopy of L3 demonstrated binding in the region where the cuticle separates during molting, in the channels connecting the esophagus to the cuticle, and in the basal lamina surrounding the esophagus and the body cavity. Among subjects from areas where this organism is endemic specific humoral and cellular immune responses to recombinant protein were observed in both PI and infected subjects, whereas responses were not observed among subjects who had not been exposed to O. volvulus. Despite the absence of differential responsiveness in parasite-exposed human populations, when the recombinant was tested for protective efficacy in a mouse chamber model, a reduction in survival of larvae by ca. 50% was seen. This observation provides support for the further study of this parasite enzyme as a vaccine candidate in larger animal models.

Amino Acid Sequence↗
PubMed2002

Activity of azithromycin against Leishmania major in vitro and in vivo.

Azithromycin, an azalide antibiotic of the macrolide family, concentrates in the tissues and especially in macrophages. Because Leishmania parasites reside in these cells, we tested this antibiotic for a possible antileishmanial activity in vitro and in vivo. Azithromycin decreased the Leishmania major promastigote count in cell-free cultures at log phase approximately 50-fold. In macrophage cultures infected with L. major amastigotes, azithromycin caused a significant decrease in parasite levels with an ED50 of 12 microg/ml. The activity in vivo was evaluated after infection of the footpads of susceptible BALB/cByJ mice and resistant C57BL/6J mice with L. major. Treatment of BALB/cByJ mice with azithromycin, 100 to 200 mg/kg/d, resulted in a significant decrease in lesion size and in the number of parasites per lesion, whereas no effect was seen in the treated C57BL/6J mice. Azithromycin has activity against L. major in vitro and in vivo. Given the severity of the disease and the limitations of the available therapeutic agents, azithromycin may have a significant role in the treatment of this group of diseases.

Animals↗
PubMed2001

Identification of the key regions within the mouse pro-alpha 2(I) collagen gene far-upstream enhancer.

Studies using transgenic mice have shown that the mouse pro-alpha2(I) collagen gene contains a far-upstream enhancer, which directs expression in the majority of collagen I-producing cells during development and in response to tissue injury. In this study, we have investigated the minimal functional region required for the enhancer effect and studied the role of the three hypersensitive sites (HS3-HS5) that overlap this region. The results of deletion experiments indicate that the minimal functional unit of this enhancer is a 1.5-kb region between -17.0 and -15.45 kb from the transcription start site. This region includes the core sequences of HS3 and HS4 but not HS5. The HS4 sequences are essential for the functional integrity of the enhancer, whereas HS3 represents tissue-specific elements that direct expression in mesenchymal cells of internal tissues and body wall muscles. The HS3 region appears to bind a complex of transcription factors illustrated by large regions of protected sequences. A 400-bp sequence located between -17.0 and -16.6 is also essential for the enhancer because its deletion results in increased susceptibility to the chromatin environment.

Animals↗