Medical Biology - Research Publications
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ItemNo Preview AvailableAgm1/Pgm-3-mediated sugar nucleotide synthesis is essential for hematopoiesis and development(AMER SOC MICROBIOLOGY, 2007-08)Carbohydrate modification of proteins includes N-linked and O-linked glycosylation, proteoglycan formation, glycosylphosphatidylinositol anchor synthesis, and O-GlcNAc modification. Each of these modifications requires the sugar nucleotide UDP-GlcNAc, which is produced via the hexosamine biosynthesis pathway. A key step in this pathway is the interconversion of GlcNAc-6-phosphate (GlcNAc-6-P) and GlcNAc-1-P, catalyzed by phosphoglucomutase 3 (Pgm3). In this paper, we describe two hypomorphic alleles of mouse Pgm3 and show there are specific physiological consequences of a graded reduction in Pgm3 activity and global UDP-GlcNAc levels. Whereas mice lacking Pgm3 die prior to implantation, animals with less severe reductions in enzyme activity are sterile, exhibit changes in pancreatic architecture, and are anemic, leukopenic, and thrombocytopenic. These phenotypes are accompanied by specific rather than wholesale changes in protein glycosylation, suggesting that while universally required, the functions of certain proteins and, as a consequence, certain cell types are especially sensitive to reductions in Pgm3 activity.
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ItemNo Preview AvailableMof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture(AMER SOC MICROBIOLOGY, 2008-08)Acetylation of histone tails is a hallmark of transcriptionally active chromatin. Mof (males absent on the first; also called MYST1 or KAT8) is a member of the MYST family of histone acetyltransferases and was originally discovered as an essential component of the X chromosome dosage compensation system in Drosophila. In order to examine the role of Mof in mammals in vivo, we generated mice carrying a null mutation of the Mof gene. All Mof-deficient embryos fail to develop beyond the expanded blastocyst stage and die at implantation in vivo. Mof-deficient cell lines cannot be derived from Mof(-/-) embryos in vitro. Mof(-/-) embryos fail to acetylate histone 4 lysine 16 (H4K16) but have normal acetylation of other N-terminal histone lysine residues. Mof(-/-) cell nuclei exhibit abnormal chromatin aggregation preceding activation of caspase 3 and DNA fragmentation. We conclude that Mof is functionally nonredundant with the closely related MYST histone acetyltransferase Tip60. Our results show that Mof performs a different role in mammals from that in flies at the organism level, although the molecular function is conserved. We demonstrate that Mof is required specifically for the maintenance of H4K16 acetylation and normal chromatin architecture of all cells of early male and female embryos.
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ItemNo Preview AvailableParasite-specific IgG response and peripheral blood eosinophil count following albendazole treatment for presumed chronic strongyloidiasis(OXFORD UNIV PRESS INC, 2006)BACKGROUND: In developed countries, asymptomatic chronic Strongyloides stercoralis infection occurs in immigrants from endemic regions of the world. Accurate and reliable means of diagnosis and follow-up are required for effective management. The role of S stercoralis enzyme-linked immunosorbent assay (ELISA) in this context was examined. METHODS: In this study, 95 asymptomatic Laotian immigrants living in Melbourne, Australia, for an average of 12 years, were screened for S stercoralis infection using stool microscopy, eosinophil count, and serology by ELISA. Twenty-two patients with a positive ELISA were treated with albendazole, 400 mg twice daily for 3 days, and monitored with serology, fecal microscopy, and eosinophil counts at 2, 6, 12, and 36 months after treatment. RESULTS: Patients with moderately reactive baseline ELISA and no eosinophilia had no significant change in either measure over the 36 months of follow-up. All patients with a strongly reactive baseline ELISA showed a reduction in reactivity over the first 6 months of treatment. However, in 50% of these patients, reactivity increased between 12 and 36 months, suggesting treatment failure and relapse of infection. One patient had confirmed treatment failure based on the development of hyperinfection syndrome. CONCLUSION: The results support evidence that serology is a valuable tool in monitoring treatment responses in patients with suspected strongyloidiasis and highlights the need to ensure that S stercoralis is completely eradicated after treatment.
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ItemNo Preview AvailableAssessment of susceptibility of Plasmodium falciparum to chloroquine, quinine, mefloquine, sulfadoxine-pyrimethamine and artemisinin in southern Viet Nam(ROYAL SOC TROPICAL MEDICINE, 2001)Resistance to antimalarial chemotherapy is a major concern for malaria control in Viet Nam. In this study undertaken in 1998, 65 patients with uncomplicated Plasmodium falciparum malaria were monitored for 28 days after completion of a 5-day treatment course with artemisinin. Overall 36.9% (24/65) of patients had recurrent parasitaemia during the surveillance period. P. falciparum isolates were tested for sensitivity in vitro to chloroquine, mefloquine, quinine, sulfadoxine-pyrimethamine and results were compared to those from a similar study in 1995. Increased parasite sensitivity to sulfadoxine-pyrimethamine, chloroquine and quinine was demonstrated, with significantly lower mean EC50 and EC99 values in 1998 compared to 1995. Parasite sensitivity to mefloquine did not differ significantly in the 2 surveys. Isolates were also tested for sensitivity in vitro to artemisinin in the 1998 survey. The mean EC50 was 0.03 mumol/L and the EC99 was 0.94 mumol/L. Parasite sensitivity to artemisinin will need to be monitored in view of its increasing use in Viet Nam.
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ItemPrevalence of polymorphisms in DHFR, DHPS, PFMDR1 and PFCRT genes of Plasmodium falciparum isolates in Quang Tri Province, Vietnam(SEAMEO TROPMED Network, 2008-11)In 2002 an antimalarial drug resistance survey was carried out in a seasonally endemic area of Vietnam. Sulfadoxine/pyrimethamine (S/P) was the standard treatment recommended for uncomplicated Plasmodium falciparum malaria in that area at the time. Early or late treatment failure as defined by WHO was observed in 14.9% (7/47) of patients. Molecular analysis of treatment failure isolates identified that 5/6 carried two or more dhfr and dhps polymorphisms associated with S/P resistance. Chloroquine resistance-associated polymorphisms occurred in 38.5% (15/39) of the isolates. These results support the move to artemisinin-based combination therapy for malaria in Vietnam.
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ItemNo Preview AvailableAnemia, iron deficiency, meat consumption, and hookworm infection in women of reproductive age in northwest Vietnam(AMER SOC TROP MED & HYGIENE, 2008-03)Iron deficiency anemia poses an important public health problem for women of reproductive age living in developing countries. We assessed the prevalence of iron deficiency and anemia and associated risk factors in a community-based sample of women living in a rural province of northwest Vietnam. A cross-sectional survey, comprised of written questionnaires and laboratory analysis of hemoglobin (Hb), ferritin, transferrin receptor, and stool hookworm egg count, was undertaken, and the soluble transferrin receptor/log ferritin index was calculated. Of 349 non-pregnant women, 37.53% were anemic (Hb < 12 g/dL), and 23.10% were iron deficient (ferritin < 15 ng/L). Hookworm infection was present in 78.15% of women, although heavy infection was uncommon (6.29%). Iron deficiency was more prevalent in anemic than non-anemic women (38.21% versus 14.08%, P < 0.001). Consumption of meat at least three times a week was more common in non-anemic women (51.15% versus 66.67%, P = 0.042). Mean ferritin was lower in anemic women (18.99 versus 35.66 ng/mL, P < 0.001). There was no evidence of a difference in prevalence (15.20% versus 17.23%, P = 0.629) or intensity (171.07 versus 129.93 eggs/g, P = 0.412) of hookworm infection between anemic and non-anemic women. Although intensity of hookworm infection and meat consumption were associated with indices of iron deficiency in a multiple regression model, their relationship with hemoglobin was not significant. Anemia, iron deficiency, and hookworm infection were prevalent in this population. Intake of meat was more clearly associated with hemoglobin and iron indices than hookworm. An approach to addressing iron deficiency in this population should emphasize both iron supplementation and deworming.
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ItemCell cycle genes are the evolutionarily conserved targets of the E2F4 transcription factor.(Public Library of Science (PLoS), 2007-10-24)Maintaining quiescent cells in G0 phase is achieved in part through the multiprotein subunit complex known as DREAM, and in human cell lines the transcription factor E2F4 directs this complex to its cell cycle targets. We found that E2F4 binds a highly overlapping set of human genes among three diverse primary tissues and an asynchronous cell line, which suggests that tissue-specific binding partners and chromatin structure have minimal influence on E2F4 targeting. To investigate the conservation of these transcription factor binding events, we identified the mouse genes bound by E2f4 in seven primary mouse tissues and a cell line. E2f4 bound a set of mouse genes that was common among mouse tissues, but largely distinct from the genes bound in human. The evolutionarily conserved set of E2F4 bound genes is highly enriched for functionally relevant regulatory interactions important for maintaining cellular quiescence. In contrast, we found minimal mRNA expression perturbations in this core set of E2f4 bound genes in the liver, kidney, and testes of E2f4 null mice. Thus, the regulatory mechanisms maintaining quiescence are robust even to complete loss of conserved transcription factor binding events.
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ItemPrevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea.(MDPI AG, 2007-02)Chemotherapy-induced diarrhea (cid) is a common side effect of cancer treatment and can cause significant morbidity and mortality. Diarrhea is frequently severe enough to require a dose reduction of, a delay in, or a discontinuation of chemotherapy. Diarrhea-associated mortality has been reported to be as high as 3.5% in clinical trials of irinotecan and bolus 5-fluorouracil in colorectal cancer. The frequency of cid and its impact on patient management are frequently under-recognized in clinical practice.A Canadian working group, consisting of medical oncologists and an oncology pharmacist, was formed in 2001 to review the optimal approach to managing cid and to identify and implement new areas of research. The recommendations that follow are the result of the group's work.Acute medical management of cid includes loperamide or diphenoxylate as first-line agents. Subcutaneous octreotide is recommended for intractable grade 2 diarrhea and may be considered for grade 1 cid that does not resolve with high-dose loperamide. Hospitalization is recommended for patients with grades 3 and 4 cid; in-hospital care includes rehydration, antibiotic therapy, and octreotide.A chemotherapy dose reduction is generally advised for patients who have experienced grade 3 or 4 diarrhea in a previous chemotherapy cycle. If a dose reduction is not desired, prophylaxis with intramuscular long-acting release octreotide may be considered.The foregoing recommendations are based on expert opinion and require validation in prospective clinical trials.
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ItemInterferon-induced protein IFIT4 is associated with systemic lupus erythematosus and promotes differentiation of monocytes into dendritic cell-like cells(BIOMED CENTRAL LTD, 2008)INTRODUCTION: Using oligonucleotide microarray, many IFN-inducible genes have been found to be highly expressed in peripheral blood mononuclear cells (PBMCs) from most patients with systemic lupus erythematosus (SLE). Among these IFN-inducible genes, IFN-induced protein with tetratricopeptide repeats 4 (IFIT4) is a novel gene whose function is unknown. METHODS: In this study we examined the role played by IFIT4 in monocyte differentiation and the correlation between IFIT4 expression and the clinical manifestation of SLE. To this end, we used plasmid transfection, flow cytometry, mixed leucocyte responses, ELISA, quantitative RT-PCR and Western blotting. RESULTS: We found that both IFIT4 mRNA and protein expression levels were significantly higher in PBMCs and monocytes from SLE patients than in those from healthy control individuals. IFIT4 expression was positively correlated with antinuclear antibodies, anti-double-stranded DNA, and anti-Sm auto-immune antibodies in SLE. Patients with SLE exhibiting higher expression of IFIT4 had a higher prevalence of leucopenia, thrombocytopenia and C3/C4 decrease. IFIT4 protein was localized exclusively to the cytoplasm, and it was significantly upregulated by IFN-alpha in normal PBMCs. To determine the role played by IFIT4 in monocyte differentiation, the monocytic cell line THP-1 was transfected with pEGFP-IFIT4 expression plasmid and stimulated with granulocyte-macrophage colony-stimulating factor/IL-4 to generate IFIT4-primed dendritic cell-like cells (DCLCs). IFIT4-primed DCLCs acquired morphological characteristics of dendritic cells more quickly, with greater resemblance to dendritic cells, as compared with DCLCs primed with pEGFP-C1 control plasmid trasfection. Furthermore, they exhibited higher expressions of CD40, CD86, CD80, HLA-DR and CD83, along with lower expression of CD14; increased IL-12 secretion; and an increased ability to stimulate T-cell proliferation. In addition, IFIT4-primed DCLCs enhanced IFN-gamma secretion (about 2.4-fold) by T cells compared with controls. CONCLUSION: Our findings suggest that IFIT4 might play roles in promoting monocyte differentiation into DCLCs and in directing DCLCs to modulate T-helper-1 cell differentiation; these actions might contribute to the autoimmunity and pathogenesis of SLE.
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ItemThe early progenitors of mouse dendritic cells and plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors expressing Flt3.(Rockefeller University Press, 2003-07-21)Flt3 ligand (Flt3L) is a growth factor for hemopoietic progenitors and can promote the expansion of both conventional dendritic cells (DCs) and plasmacytoid predendritic cells (p-preDCs). The cells responding to Flt3L treatment and the precursors for the DCs and p-preDCs had not been fully characterized. We examined different mouse bone marrow (BM) hemopoietic precursor populations for the surface expression of Flt3 and tested them for early DC and p-preDC precursor activity. Most DC precursor activity, other than that given by multipotent hemopoietic stem cells, was within the downstream precursors expressing Flt3. The majority of mouse BM common lymphoid precursors expressed high levels of Flt3 and these were the most efficient precursors of both DCs and p-preDCs. In contrast, only a small proportion of the common myeloid precursors (CMPs) expressed Flt3, but the precursor activity for both DCs and p-preDCs was within this minor Flt3+ CMP fraction. The granulocyte and macrophage precursors and pro-B cells did not express Flt3 and had no DC or p-preDC precursor activity. These findings demonstrate that the early precursors for all DC subtypes are within the BM Flt3+ precursor populations, regardless of their lymphoid or myeloid lineage orientation.