375 research outputs found
CELLULAR EVENTS IN THE IMMUNE RESPONSE : ANALYSIS AND IN VITRO RESPONSE OF MOUSE SPLEEN CELL POPULATIONS SEPARATED BY DIFFERENTIAL FLOTATION IN ALBUMIN GRADIENTS
Cell suspensions from the spleens of normal mice or mice injected with sheep erythrocytes were separated on a discontinous bovine serum albumin density gradient. Four bands or subpopulations were obtained and were assayed for antibody-forming cells, and for antigen-sensitive precursor cells. The antibody-forming cells were assayed by the hemolytic plaque assay and the antigen-sensitive precursors were assayed by the number of plaque-forming cells which developed after 3 or 5 day's culture with antigen. It was found that both antibody-forming cells and their precursors were present in the denser region of the gradient when spleen cell suspensions were taken from unimmunized mice. In contrast, both antibody-forming cells and precursors floated to the top in cell suspensions from mice sacrificed 1, 2, or 3 days after antigen injection. The change in density was detectable as early as 12 hr and was complete by 18 hr. The cell which changed in density was specific for the antigen that brought about that change. The significance of these findings is discussed
Design Studies Suggested by an Abstract Model for Medical Information System
We have developed a formal model of a database system that is unusual in that it has the ability to represent information about its own structure and to insure semantic consistency. The model distinguishes general laws from instances of events and objects, but many of its mechanisms serve both categories of information. The model form a substrate upon which an information structure appropriate to neonatology is being developed. Some example queries are shown and a design study for an associative memory suggested by the model is described briefly
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Effect of Protease Inhibitors on Steady-State Pharmacokinetics of Oral Norethindrone Contraception in HIV-Infected Women
OBJECTIVE: Pharmacokinetic interactions exist between combined
oral contraceptives and protease inhibitors (PI). However, such
information is lacking for progestin-only oral contraception. We
sought to define the steady-state pharmacokinetic interaction between
norethindrone (NET) and PI in HIV-infected women.
METHODS AND DESIGN: We conducted an open-label, prospective,
nonrandomized trial to characterize the steady-state pharmacokinetics
of serum NET in HIV-infected women receiving PI compared
with a control group of HIV-infected women receiving other
noninteracting drugs. After 21 days of 0.35 mg of NET ingestion
once daily, serial serum samples were obtained at 0, 1, 2, 3, 4, 6, 8,
12, 24, 48, and 72 hours. The area under the curve between 0 and
72 hours after ingestion was calculated by trapezoidal approximation.
RESULTS: Thirty-five women were enrolled, 2 withdrew. Sixteen
women in the PI group and 17 controls completed the study. NET
half-life and maximum concentration were not significantly different
between the 2 groups. Minimum concentration of NET was significantly
higher in the PI group (P = 0.01). The ratio of the geometric
mean NET area under the curve in the PI group compared with controls
was 1.5 (90% confidence interval: 1.21 to 1.86). NET serum
concentrations were significantly higher in HIV-infected women taking
a PI compared with controls (P = 0.004).
CONCLUSIONS: Coadministration of PI inhibits NET metabolism as
shown by higher serum NET area under the curve levels, a surrogate
marker for therapeutic contraceptive efficacy. This study supports
the increased utilization of progestin-only pills in HIV-infected
women receiving certain PI regimens.Keywords: norethindrone, HIV, efficacy, hormonal contraception, drug interactions, pharmacokinetics, progestin only pills, protease inhibitor, contraceptio
Injectable and Oral Contraceptive Use and Cancers of the Breast, Cervix, Ovary, and Endometrium in Black South African Women: CaseβControl Study
A case-control study conducted in South Africa provides new estimates of the risk of specific cancers of the female reproductive system associated with use of injectable and oral contraceptives
Effect of oral contraceptive with and without associated estriol on ultrasound measurements of breast fibroadenoma: randomized clinical trial
Prolactin serum levels and breast cancer: relationships with risk factors and tumour characteristics among pre- and postmenopausal women in a population-based caseβcontrol study from Poland
Gene expression during normal and FSHD myogenesis
<p>Abstract</p> <p>Background</p> <p>Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35. Within each repeat unit is a gene, <it>DUX4</it>, that can encode a protein containing two homeodomains. A <it>DUX4 </it>transcript derived from the last repeat unit in a contracted array is associated with pathogenesis but it is unclear how.</p> <p>Methods</p> <p>Using exon-based microarrays, the expression profiles of myogenic precursor cells were determined. Both undifferentiated myoblasts and myoblasts differentiated to myotubes derived from FSHD patients and controls were studied after immunocytochemical verification of the quality of the cultures. To further our understanding of FSHD and normal myogenesis, the expression profiles obtained were compared to those of 19 non-muscle cell types analyzed by identical methods.</p> <p>Results</p> <p>Many of the ~17,000 examined genes were differentially expressed (> 2-fold, <it>p </it>< 0.01) in control myoblasts or myotubes vs. non-muscle cells (2185 and 3006, respectively) or in FSHD vs. control myoblasts or myotubes (295 and 797, respectively). Surprisingly, despite the morphologically normal differentiation of FSHD myoblasts to myotubes, most of the disease-related dysregulation was seen as dampening of normal myogenesis-specific expression changes, including in genes for muscle structure, mitochondrial function, stress responses, and signal transduction. Other classes of genes, including those encoding extracellular matrix or pro-inflammatory proteins, were upregulated in FSHD myogenic cells independent of an inverse myogenesis association. Importantly, the disease-linked <it>DUX4 </it>RNA isoform was detected by RT-PCR in FSHD myoblast and myotube preparations only at extremely low levels. Unique insights into myogenesis-specific gene expression were also obtained. For example, all four Argonaute genes involved in RNA-silencing were significantly upregulated during normal (but not FSHD) myogenesis relative to non-muscle cell types.</p> <p>Conclusions</p> <p><it>DUX4</it>'s pathogenic effect in FSHD may occur transiently at or before the stage of myoblast formation to establish a cascade of gene dysregulation. This contrasts with the current emphasis on toxic effects of experimentally upregulated <it>DUX4 </it>expression at the myoblast or myotube stages. Our model could explain why <it>DUX4</it>'s inappropriate expression was barely detectable in myoblasts and myotubes but nonetheless linked to FSHD.</p
Zinc Coordination Is Required for and Regulates Transcription Activation by Epstein-Barr Nuclear Antigen 1
Epstein-Barr Nuclear Antigen 1 (EBNA1) is essential for Epstein-Barr virus to immortalize naΓ―ve B-cells. Upon binding a cluster of 20 cognate binding-sites termed the family of repeats, EBNA1 transactivates promoters for EBV genes that are required for immortalization. A small domain, termed UR1, that is 25 amino-acids in length, has been identified previously as essential for EBNA1 to activate transcription. In this study, we have elucidated how UR1 contributes to EBNA1's ability to transactivate. We show that zinc is necessary for EBNA1 to activate transcription, and that UR1 coordinates zinc through a pair of essential cysteines contained within it. UR1 dimerizes upon coordinating zinc, indicating that EBNA1 contains a second dimerization interface in its amino-terminus. There is a strong correlation between UR1-mediated dimerization and EBNA1's ability to transactivate cooperatively. Point mutants of EBNA1 that disrupt zinc coordination also prevent self-association, and do not activate transcription cooperatively. Further, we demonstrate that UR1 acts as a molecular sensor that regulates the ability of EBNA1 to activate transcription in response to changes in redox and oxygen partial pressure (pO2). Mild oxidative stress mimicking such environmental changes decreases EBNA1-dependent transcription in a lymphoblastoid cell-line. Coincident with a reduction in EBNA1-dependent transcription, reductions are observed in EBNA2 and LMP1 protein levels. Although these changes do not affect LCL survival, treated cells accumulate in G0/G1. These findings are discussed in the context of EBV latency in body compartments that differ strikingly in their pO2 and redox potential
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