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Biomedical subjects

S A Jones

Publications and source records attributed to S A Jones.

At least 37 records · Page 2Linked to original sources
PubMed2001

Local hemodynamics affect monocytic cell adhesion to a three-dimensional flow model coated with E-selectin.

Monocyte adhesion to the endothelium depends on concentrations of receptors/ligands, local concentrations of chemoattractants, monocyte transport to the endothelial surface and hemodynamic forces. Monocyte adhesion to the inert surface of a three-dimensional perfusion model was shown to correlate inversely with wall shear stress, but was also affected by flow patterns which influenced the near-wall cell availability. We hypothesized that (a) under the same flow conditions, insolubilized E-selectin on the model's surface may mediate adhesive interactions at higher wall shear stresses, compared to an uncoated model, and (b) pulsatile flow may modify the adhesion profile obtained under steady flow. An axisymmetric flow model with a stenosis and a sudden expansion produced a range of wall shear stresses and a separated flow with recirculation and reattachment. Pre-activated U937 cells were perfused through the model under either steady (Re = 100, 140) or pulsatile (Remean = 107) flow. The velocity field was characterized through computational fluid dynamics and validated by inert particle tracking. Surface E-selectin greatly increased cell adhesion in all regions at Re = 100 and 140, compared to an uncoated model under the same flow conditions. In regions where the cells near the wall were abundant (taper and stenosis), adhesion to E-selectin correlated with the reciprocal of local wall shear stress when flow was steady. Pulsatile flow distributed the adherent cells more evenly throughout the coated model. Hence, characterizing both the local hemodynamics and the biological activity on the vessel wall is important in leukocyte adhesion.

Cell Adhesion↗
PubMed2001

A novel phosphorylcholine-coated contact lens for extended wear use.

The preparation and characterisation of a new phosphorylcholine (PC)-coated silicone hydrogel contact lens for use in extended wear is described. The Michael-type addition of amines to acrylates forms the basis of the synthesis of a novel silicone-based macromer with hydrophilic functionality. It is demonstrated that this macromer can be combined with other silicone-based monomers, hydrophilic monomers and crosslinker to produce a contact lenses formulation. Examples of lenses with water contents of 33% and 46% are illustrated and their properties compared to other commercially available lenses. Materials with comparatively low modulus (<0.3 MPa) and adequate tear strength (>2-4MPa) with excellent elongation to break (>200%) can be obtained using this technology. In addition to the mechanical aspects. both the oxygen and solute permeabilities of the material can be controlled by the hydrophilic: hydrophobic monomer balance in the formulation. to obtain materials with attributes suitable for extended wear use. The PC coating is achieved by means of an in-mould coating (IMC) technique that produces a uniform and stable surface as determined by staining and XPS. The coating imparts both improved lens wettability (advancing contact angle of approximately 50 with virtually no hysteresis) and lower protein adsorption relative to the uncoated lens.

Adsorption↗
PubMed2001

Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation.

During acute inflammation, leukocyte recruitment is characterized by an initial infiltration of neutrophils, which are later replaced by a more sustained population of mononuclear cells. Based on both clinical and experimental evidence, we present a role for IL-6 and its soluble receptor (sIL-6R) in controlling this pattern of leukocyte recruitment during peritoneal inflammation. Liberation of sIL-6R from the initial neutrophil infiltrate acts as a regulator of CXC and CC chemokine expression, which contributes to a suppression of neutrophil recruitment and the concurrent attraction of mononuclear leukocytes. Soluble IL-6R-mediated signaling is therefore an important intermediary in the resolution of inflammation and supports transition between the early predominantly neutrophilic stage of an infection and the more sustained mononuclear cell influx.

Animals↗
PubMed2001

The soluble interleukin 6 receptor: mechanisms of production and implications in disease.

Interleukin 6 (IL-6) performs a prominent role during disease and has been described as both a pro- and anti-inflammatory cytokine. A key feature in the regulation of IL-6 responses has been the identification of a soluble interleukin 6 receptor (sIL-6R), which forms a ligand-receptor complex with IL-6 that is capable of stimulating a variety of cellular responses including proliferation, differentiation and activation of inflammatory processes. Elevated sIL-6R levels have been documented in numerous clinical conditions indicating that its production is coordinated as part of a disease response. Thus, sIL-6R has the potential to regulate both local and systemic IL-6-mediated events. This review will outline the central role of sIL-6R in the coordination of IL-6 responses. Details relating to the mechanisms of sIL-6R production will be provided, while the potential significance of sIL-6R during the development of clinical conditions will be emphasized. We want to convey, therefore, that when thinking about the inflammatory capability of IL-6, it is essential to consider not only the action of IL-6 itself, but also the effect sIL-6R may have on cellular processes.

Alternative Splicing↗
PubMed2001

Review of data describing outcomes that are used to assess changes in quality of life after reduction mammaplasty.

Although plastic surgeons have empirically "known" of the benefits of reduction mammaplasty for their patients, a paucity of outcome studies have been reported. For this study, an attempt to perform a meta-analysis of outcomes in reduction mammaplasty was undertaken. A computer literature search was performed of the MEDLINE database for the period between 1966 and September of 1997 for the Medical Subject Headings mammaplasty and outcome measures. Reference lists were used for additional reports. No trials were identified that met the criteria for meta-analysis. Seventeen publications met less restrictive review criteria that evaluated quality-of-life outcome measures. A systematic evaluation of patient-focused outcome measures demonstrated that consistent improvement in physical symptoms was found across most studies, as was a high degree of patient satisfaction (78 to 95 percent very or moderately satisfied), and some have shown improvement in body image and psychological well-being. However, although this review does identify consistent improvements in patient quality of life after reduction mammaplasty, inconsistencies among study designs do not allow formal meta-analysis.

Adolescent↗
PubMed2001

Pulsatile flow in an end-to-side vascular graft model: comparison of computations with experimental data.

Various hemodynamic factors have been implicated in vascular graft intimal hyperplasia, the major mechanism contributing to chronic failure of small-diameter grafts. However, a thorough knowledge of the graft flow field is needed in order to determine the role of hemodynamics and how these factors affect the underlying biological processes. Computational fluid dynamics offers much more versatility and resolution than in vitro or in vivo methods, yet computations must be validated by careful comparison with experimental data. Whereas numerous numerical and in vitro simulations of arterial geometries have been reported, direct point-by-point comparisons of the two techniques are rare in the literature. We have conducted finite element computational analyses for a model of an end-to-side vascular graft and compared the results with experimental data obtained using laser-Doppler velocimetry. Agreement for velocity profiles is found to be good, with some clear differences near the recirculation zones during the deceleration and reverse-flow segments of the flow waveform. Wall shear stresses are determined from velocity gradients, whether by computational or experimental methods, and hence the agreement for this quantity, while still good, is less consistent than for velocity itself from the wall shear stress numerical results, we computed four variables that have been cited in the development of intiimal hyperplasia-the time-averaged wall shear stress, an oscillating shear index, and spatial and temporal wall shear stress gradients in order to illustrate the versatility of numerical methods. We conclude that the computational approach is a valid alternative to the experimental approach for quantitative hemodynamic studies. Where differences in velocity were found by the two methods, it was generally attributed to the inability of the numerical method to model the fluid dynamics when flow conditions are destabilizing. Differences in wall shear, in the absence of destabilizing phenomena, were more likely to be caused by difficulties in calculating wall shear from relatively low resolution in vitro data.

Anastomosis, Surgical↗
PubMed2001

High-throughput detection of West Nile virus RNA.

The recent outbreaks of West Nile virus (WNV) in the northeastern United States and other regions of the world have made it essential to develop an efficient protocol for surveillance of WNV. In the present report, we describe a high-throughput procedure that combines automated RNA extraction, amplification, and detection of WNV RNA. The procedure analyzed 96 samples in approximately 4.5 h. A robotic system, the ABI Prism 6700 Automated Nucleic Acid workstation, extracted RNA and set up reactions for real-time reverse transcription (RT)-PCR in a 96-well format. The robot extracted RNA with a recovery as efficient as that of a commercial RNA extraction kit. A real-time RT-PCR assay was used to detect and quantitate WNV RNA. Using in vitro transcribed RNA, we estimated the detection limit of the real-time RT-PCR to be approximately 40 copies of RNA. A standard RT-PCR assay was optimized to a sensitivity similar to that of the real-time RT-PCR. The standard assay can be reliably used to test a small number of samples or to confirm previous test results. Using internal primers in a nested RT-PCR, we increased the sensitivity by approximately 10-fold compared to that of the standard RT-PCR. The results of the study demonstrated for the first time that the use of an automated system for the purpose of large-scale viral RNA surveillance dramatically increased the speed and efficiency of sample throughput for diagnosis.

Animals↗
PubMed2001

Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids.

The farnesoid X-activated receptor (FXR; NR1H4), a member of the nuclear hormone receptor superfamily, induces gene expression in response to several bile acids, including chenodeoxycholic acid. Here we used suppression subtractive hybridization to identify apolipoprotein C-II (apoC-II) as an FXR target gene. Retroviral expression of FXR in HepG2 cells results in induction of the mRNA encoding apoC-II in response to several FXR ligands. EMSAs demonstrate that recombinant FXR and RXR bind to two FXR response elements that are contained within two important distal enhancer elements (hepatic control regions) that lie 11 kb and 22 kb upstream of the transcription start site of the apoC-II gene. A luciferase reporter gene containing the hepatic control region or two copies of the wild-type FXR response element was activated when FXR-containing cells were treated with FXR ligands. In addition, we report that hepatic expression of both apoC-II and phospholipid transfer protein mRNAs increases when mice are fed diets supplemented with cholic acid, an FXR ligand, and this induction is attenuated in FXR null mice. Finally, we observed decreased plasma triglyceride levels in mice fed cholic acid- containing diets. These results identify a mechanism whereby FXR and its ligands lower plasma triglyceride levels. These findings may have important implications in the clinical management of hyperlipidemias.

Animals↗
PubMed2000

St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.

St. John's wort (Hypericum perforatum) is an herbal remedy used widely for the treatment of depression. Recent clinical studies demonstrate that hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin, and indinavir. In this report, we show that hyperforin, a constituent of St. John's wort with antidepressant activity, is a potent ligand (K(i) = 27 nM) for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of primary human hepatocytes with hypericum extracts or hyperforin results in a marked induction of CYP3A4 expression. Because CYP3A4 is involved in the oxidative metabolism of >50% of all drugs, our findings provide a molecular mechanism for the interaction of St. John's wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realized.

Bridged Bicyclo Compounds↗
PubMed2000

Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands.

Xenobiotics induce the transcription of cytochromes P450 (CYPs) 2B and 3A through the constitutive androstane receptor (CAR; NR1I3) and pregnane X receptor (PXR; NR1I2), respectively. In this report, we have systematically compared a series of xenobiotics and natural steroids for their effects on mouse and human CAR and PXR. Our results demonstrate dual regulation of PXR and CAR by a subset of compounds that affect CYP expression. Moreover, there are marked pharmacological differences between the mouse (m) and human (h) orthologs of both CAR and PXR. For example, the planar hydrocarbon 1, 4-bis[2-(3,5-dichloropyridyl-oxy)]benzene activates mCAR and hPXR but has little or no activity on hCAR and mPXR. In contrast, the CAR deactivator androstanol activates both mouse and human PXR. Similarly, the PXR activator clotrimazole is a potent deactivator of hCAR. Using radioligand binding and fluorescence resonance energy transfer assays, we demonstrate that several of the compounds that regulate mouse and human CAR, including natural steroids, bind directly to the receptors. Our results suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse compounds. Moreover, our findings underscore the complexity in the physiologic response to xenobiotics.

Animals↗
PubMed2000

IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage.

Elevated concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) in the synovial fluids and serum of patients with arthritis have been implicated in the joint tissue destruction associated with these conditions, however studies conducted to date on the role and effects of IL-6 in the process of cartilage proteoglycan (aggrecan) catabolism are disparate. In the present study, bovine articular cartilage explants were maintained in a model organ culture system in the presence or absence of IL-1alpha or TNF-alpha, and under co-stimulation with or without IL-6 and/or sIL-6R. After measuring proteoglycan loss from the explants, the proteolytic activity and expression profiles of aggrecanase(s) was assessed for each culture condition. Stimulation of cartilage explants with IL-6 and/or sIL-6R potentiated aggrecan catabolism and release above that seen in the presence of IL-1alpha or TNF-alpha alone. This catabolism was associated with aggrecanase (but not MMP) activity, with correlative mRNA expression for aggrecanase-2.

ADAM Proteins↗
PubMed2000

A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.

Animals↗
PubMed2000

Cost-effectiveness analysis methods for the REACT Study.

The Reconditioning Exercise and Chronic Obstructive Pulmonary Disease Trial (REACT) is a two-arm randomized clinical trial designed to compare short-term versus long-term exercise intervention in terms of physical function, acute exacerbation of chronic obstructive pulmonary disease, health-related quality of life, and cost-effectiveness. Clinical trials such as REACT are now routinely paired with economic analyses, and nurses can expect to play a growing role in the conduct of these studies. This article describes a model that is useful for structuring economic evaluations of health care interventions, and illustrates a cost-effectiveness analysis that is being conducted in conjunction with the REACT study. An in-depth description of collection methods and procedures is provided, as well as a summary of recruitment and retention experience to date.

Aged↗
PubMed2000

The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution.

Transcription of genes encoding cytochrome P450 3A (CYP3A) monooxygenases is induced by a variety of xenobiotics and natural steroids. There are marked differences in the compounds that induce CYP3A gene expression between species. Recently, the mouse and human pregnane X receptor (PXR) were shown to be activated by compounds that induce CYP3A expression. However, most studies of CYP3A regulation have been performed using rabbit and rat hepatocytes. Here, we report the cloning and characterization of PXR from these two species. PXR is remarkably divergent between species, with the rabbit, rat, and human receptors sharing only approximately 80% amino acid identity in their ligand-binding domains. This sequence divergence is reflected by marked pharmacological differences in PXR activation profiles. For example, the macrolide antibiotic rifampicin, the antidiabetic drug troglitazone, and the hypocholesterolemic drug SR12813 are efficacious activators of the human and rabbit PXR but have little activity on the rat and mouse PXR. Conversely, pregnane 16alpha-carbonitrile is a more potent activator of the rat and mouse PXR than the human and rabbit receptor. The activities of xenobiotics in PXR activation assays correlate well with their ability to induce CYP3A expression in primary hepatocytes. Through the use of a novel scintillation proximity binding assay, we demonstrate that many of the compounds that induce CYP3A expression bind directly to human PXR. These data establish PXR as a promiscuous xenobiotic receptor that has diverged during evolution.

Amino Acid Sequence↗
PubMed2000

Exemestane: a novel aromatase inactivator for breast cancer.

Exemestane is a unique inactivator of the aromatase enzyme and differs from the two approved aromatase inhibitors. It is well absorbed at a daily oral dose of 25 mg and produces significant suppression of aromatase and plasma estrogen levels without androgenic side effects. Toxicity is mild with menopausal symptoms predominating. Exemestane is approved for the treatment of postmenopausal women with recurrent breast cancer. In reported clinical trials, exemestane was effective in patients failing tamoxifen, megestrol acetate, or even other aromatase inhibitors in phase II trials and was superior to megestrol acetate in a phase III randomized trial in which an early survival advantage for exemestane was observed. Studies evaluating first-line exemestane for adjuvant use and as a chemopreventive agent are underway.

Androstadienes↗