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1.
Sheila N. Balinda Pascale Ondoa Ekwaro A. Obuku Aletta Kliphuis Isaac Egau Michelle Bronze Lordwin Kasambula Rob Schuurman Nicole Spieker Tobias F. Rinke de Wit Cissy Kityo ART–A consortium 《PloS one》2016,11(1)
Background
WHO recommends regular viral load (VL) monitoring of patients on antiretroviral therapy (ART) for timely detection of virological failure, prevention of acquired HIV drug resistance (HIVDR) and avoiding unnecessary switching to second-line ART. However, the cost and complexity of routine VL testing remains prohibitive in most resource limited settings (RLS). We evaluated a simple, low–cost, qualitative viral–failure assay (VFA) on dried blood spots (DBS) in three clinical settings in Uganda.Methods
We conducted a cross–sectional diagnostic accuracy study in three HIV/AIDS treatment centres at the Joint Clinical Research Centre in Uganda. The VFA employs semi-quantitative detection of HIV–1 RNA amplified from the LTR gene. We used paired dry blood spot (DBS) and plasma with the COBASAmpliPrep/COBASTaqMan, Roche version 2 (VLref) as the reference assay. We used the VFA at two thresholds of viral load, (>5,000 or >1,000 copies/ml).Results
496 paired VFA and VLref results were available for comparative analysis. Overall, VFA demonstrated 78.4% sensitivity, (95% CI: 69.7%–87.1%), 93% specificity (95% CI: 89.7%–96.4%), 89.3% accuracy (95% CI: 85%–92%) and an agreement kappa = 0.72 as compared to the VLref. The predictive values of positivity and negativity among patients on ART for >12 months were 72.7% and 99.3%, respectively.Conclusions
VFA allowed 89% of correct classification of VF. Only 11% of the patients were misclassified with the potential of unnecessary or late switch to second–line ART. Our findings present an opportunity to roll out simple and affordable VL monitoring for HIV–1 treatment in RLS. 相似文献2.
小鼠乳腺由多种不同类型的上皮细胞构成。多潜能干细胞位于乳腺发育的顶端,是乳腺中所有分化细胞类型的来源。然而,这群多潜能乳腺干细胞此前尚未通过特定的标记基因得到鉴定,其存在性也备受争议。借助乳腺干细胞体外培养体系,从Wnt信号通路入手,发现了蛋白C受体基因Procr。在乳腺中,Procr作为一个新的Wnt信号通路的靶基因,能够标记多潜能乳腺干细胞。Procr标记乳腺基底细胞中的一个亚群,这个亚群的细胞低表达基底细胞普遍表达的角蛋白,表现出上皮–间充质转化的特性。Procr阳性的细胞在移植实验中表现出最高的乳腺重建率,体内追踪Procr阳性细胞的后代,发现Procr阳性细胞能够在发育过程中分化形成乳腺上皮的所有细胞类型。多潜能乳腺干细胞的发现结束了乳腺中多潜能干细胞存在性的争议,对乳腺癌的诊断及靶向治疗具有重大意义。 相似文献
3.
Depletion of regulatory T cells in HIV infection is associated with immune activation 总被引:15,自引:0,他引:15
Eggena MP Barugahare B Jones N Okello M Mutalya S Kityo C Mugyenyi P Cao H 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(7):4407-4414
Immune activation during chronic HIV infection is a strong clinical predictor of death and may mediate CD4(+) T cell depletion. Regulatory T cells (Tregs) are CD4(+)CD25(bright)CD62L(high) cells that actively down-regulate immune responses. We asked whether loss of Tregs during HIV infection mediates immune activation in a cross-sectional study of 81 HIV-positive Ugandan volunteers. We found that Treg number is strongly correlated with both CD4(+) and CD8(+) T cell activation. In multivariate modeling, this relationship between Treg depletion and CD4(+) T cell activation was stronger than any other clinical factor examined, including viral load and absolute CD4 count. Tregs appear to decline at different rates compared with other CD4(+) T cells, resulting in an increased regulator to helper ratio in many patients with advanced disease. We hypothesize that this skewing may contribute to T cell effector dysfunction. Our findings suggest Tregs are a major contributor to the immune activation observed during chronic HIV infection. 相似文献
4.
Mariann M. Gabrawy Reyhan Westbrook Austin King Nick Khosravian Neeraj Ochaney Tagide DeCarvalho Qinchuan Wang Yuqiong Yu Qiao Huang Adam Said Michael Abadir Cissy Zhang Pratik Khare Jennifer E. Fairman Anne Le Ginger L. Milne Fernando J. Vonhoff Jeremy D. Walston Peter M. Abadir 《Aging cell》2024,23(4):e14102
Tryptophan catabolism is highly conserved and generates important bioactive metabolites, including kynurenines, and in some animals, NAD+. Aging and inflammation are associated with increased levels of kynurenine pathway (KP) metabolites and depleted NAD+, factors which are implicated as contributors to frailty and morbidity. Contrastingly, KP suppression and NAD+ supplementation are associated with increased life span in some animals. Here, we used DGRP_229 Drosophila to elucidate the effects of KP elevation, KP suppression, and NAD+ supplementation on physical performance and survivorship. Flies were chronically fed kynurenines, KP inhibitors, NAD+ precursors, or a combination of KP inhibitors with NAD+ precursors. Flies with elevated kynurenines had reduced climbing speed, endurance, and life span. Treatment with a combination of KP inhibitors and NAD+ precursors preserved physical function and synergistically increased maximum life span. We conclude that KP flux can regulate health span and life span in Drosophila and that targeting KP and NAD+ metabolism can synergistically increase life span. 相似文献
5.
Julie E. Gleason Cissy X. Li Hana M. Odeh Valeria C. Culotta 《Journal of biological inorganic chemistry》2014,19(4-5):595-603
Candida albicans is a pathogenic yeast of important public health relevance. Virulence of C. albicans requires a copper and zinc containing superoxide dismutase (SOD1), but the biology of C. albicans SOD1 is poorly understood. To this end, C. albicans SOD1 activation was examined in baker’s yeast (Saccharomyces cerevisiae), a eukaryotic expression system that has proven fruitful for the study of SOD1 enzymes from invertebrates, plants, and mammals. In spite of the 80 % similarity between S. cerevisiae and C. albicans SOD1 molecules, C. albicans SOD1 is not active in S. cerevisiae. The SOD1 appears incapable of productive interactions with the copper chaperone for SOD1 (CCS1) of S. cerevisiae. C. albicans SOD1 contains a proline at position 144 predicted to dictate dependence on CCS1. By mutation of this proline, C. albicans SOD1 gained activity in S. cerevisiae, and this activity was independent of CCS1. We identified a putative CCS1 gene in C. albicans and created heterozygous and homozygous gene deletions at this locus. Loss of CCS1 resulted in loss of SOD1 activity, consistent with its role as a copper chaperone. C. albicans CCS1 also restored activity to C. albicans SOD1 expressed in S. cerevisiae. C. albicans CCS1 is well adapted for activating its partner SOD1 from C. albicans, but not SOD1 from S. cerevisiae. In spite of the high degree of homology between the SOD1 and CCS1 molecules in these two fungal species, there exists a species-specific barrier in CCS–SOD interactions which may reflect the vastly different lifestyles of the pathogenic versus the noninfectious yeast. 相似文献
6.
I-Ping Lee Andrew K. Evans Cissy Yang Melissa G. Works Vineet Kumar Zurine De Miguel Nathan C. Manley Robert M. Sapolsky 《PloS one》2014,9(10)
The obligate intracellular parasite, Toxoplasma gondii, disseminates through its host inside infected immune cells. We hypothesize that parasite nutrient requirements lead to manipulation of migratory properties of the immune cell. We demonstrate that 1) T. gondii relies on glutamine for optimal infection, replication and viability, and 2) T. gondii-infected bone marrow-derived dendritic cells (DCs) display both “hypermotility” and “enhanced migration” to an elevated glutamine gradient in vitro. We show that glutamine uptake by the sodium-dependent neutral amino acid transporter 2 (SNAT2) is required for this enhanced migration. SNAT2 transport of glutamine is also a significant factor in the induction of migration by the small cytokine stromal cell-derived factor-1 (SDF-1) in uninfected DCs. Blocking both SNAT2 and C-X-C chemokine receptor 4 (CXCR4; the unique receptor for SDF-1) blocks hypermotility and the enhanced migration in T. gondii-infected DCs. Changes in host cell protein expression following T. gondii infection may explain the altered migratory phenotype; we observed an increase of CD80 and unchanged protein level of CXCR4 in both T. gondii-infected and lipopolysaccharide (LPS)-stimulated DCs. However, unlike activated DCs, SNAT2 expression in the cytosol of infected cells was also unchanged. Thus, our results suggest an important role of glutamine transport via SNAT2 in immune cell migration and a possible interaction between SNAT2 and CXCR4, by which T. gondii manipulates host cell motility. 相似文献
7.
Scott M. Berry Hannah M. Pezzi Eram D. Williams Jennifer M. Loeb David J. Guckenberger Alex J. Lavanway Alice A. Puchalski Cissy M. Kityo Peter N. Mugyenyi Franklin M. Graziano David J. Beebe 《PloS one》2015,10(12)
Viral load (VL) measurements are critical to the proper management of HIV in developing countries. However, access to VL assays is limited by the high cost and complexity of existing assays. While there is a need for low cost VL assays, performance must not be compromised. Thus, new assays must be validated on metrics of limit of detection (LOD), accuracy, and dynamic range. Patient plasma samples from the Joint Clinical Research Centre in Uganda were de-identified and measured using both an existing VL assay (Abbott RealTime HIV-1) and our assay, which combines low cost reagents with a simplified method of RNA isolation termed Exclusion-Based Sample Preparation (ESP).71 patient samples with VLs ranging from <40 to >3,000,000 copies/mL were used to compare the two methods. We demonstrated equivalent LOD (~50 copies/mL) and high accuracy (average difference between methods of 0.08 log, R2 = 0.97). Using expenditures from this trial, we estimate that the cost of the reagents and consumables for this assay to be approximately $5 USD. As cost is a significant barrier to implementation of VL testing, we anticipate that our assay will enhance access to this critical monitoring test in developing countries. 相似文献
8.
9.
Human immunodeficiency virus-specific responses in adult Ugandans: patterns of cross-clade recognition 下载免费PDF全文
Barugahare B Baker C K'Aluoch O Donovan R Elrefaei M Eggena M Jones N Mutalya S Kityo C Mugyenyi P Cao H 《Journal of virology》2005,79(7):4132-4139
Human immunodeficiency virus (HIV) or AIDS is currently the leading cause of death in Uganda, with at least three HIV clades (subtypes) accounting for most new infections. Whether an effective vaccine formulated on viruses from a single clade will be able to protect against infection from other local clades remains unresolved. We examined the T-cell immune responses from a cohort of HIV-seropositive individuals in Uganda with predominantly clade A and D infections. Surprisingly, we observed similar frequencies of cross-clade T-cell responses to the gag, env, and nef regions. Our data suggest that the level of viral sequence variability between distinct HIV strains does not predict the degree of cross-clade responses. High sequence homologies were also observed between consensus peptides and sequences from viral isolates, supporting the use of consensus amino acid sequences to identify immunogenic regions in studies of large populations. 相似文献
10.
Sujal M. Parikh Ekwaro A. Obuku Sarah A. Walker Aggrey S. Semeere Brandon J. Auerbach James G. Hakim Harriet Mayanja-Kizza Peter N. Mugyenyi Robert A. Salata Cissy M. Kityo 《PloS one》2013,8(10)