Translating science into improved health.
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Diet↗
Biomedical subjects
G Cannon
Publications and source records attributed to G Cannon.
Nonproliferating bystander CD4+ T cells lacking activation markers support HIV replication during immune activation.
HIV replicates primarily in lymphoid tissue and immune activation is a major stimulus in vivo. To determine the cells responsible for HIV replication during Ag-driven T cell activation, we used a novel in vitro model employing dendritic cell presentation of superantigen to CD4(+) T cells. Dendritic cells and CD4(+) T cells are the major constituents of the paracortical region of lymphoid organs, the main site of Ag-specific activation and HIV replication. Unexpectedly, replication occurred in nonproliferating bystander CD4(+) T cells that lacked activation markers. In contrast, activated Ag-specific cells were relatively protected from infection, which was associated with CCR5 and CXC chemokine receptor 4 down-regulation. The finding that HIV replication is not restricted to highly activated Ag-specific CD4(+) T cells has implications for therapy, efforts to eradicate viral reservoirs, immune control of HIV, and Ag-specific immune defects.
Antigen Presentation↗
Digital processing of radiographic images from PACS to publishing.
Several studies have addressed the implications of filmless radiologic imaging on telemedicine, diagnostic ability, and electronic teaching files. However, many publishers still require authors to submit hard-copy images for publication of articles and textbooks. This study compares the quality digital images directly exported from picture archive and communications systems (PACS) to images digitized from radiographic film. The authors evaluated the quality of publication-grade glossy photographs produced from digital radiographic images using 3 different methods: (1) film images digitized using a desktop scanner and then printed, (2) digital images obtained directly from PACS then printed, and (3) digital images obtained from PACS and processed to improve sharpness prior to printing. Twenty images were printed using each of the 3 different methods and rated for quality by 7 radiologists. The results were analyzed for statistically significant differences among the image sets. Subjective evaluations of the filmless images found them to be of equal or better quality than the digitized images. Direct electronic transfer of PACS images reduces the number of steps involved in creating publication-quality images as well as providing the means to produce high-quality radiographic images in a digital environment.
Analysis of Variance↗
Molecular surveillance of the incidence of Taylorella equigenitalis and Pseudomonas aeruginosa from horses in Ireland by sequence-specific PCR.
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Animals↗
HIV gag mRNA transfection of dendritic cells (DC) delivers encoded antigen to MHC class I and II molecules, causes DC maturation, and induces a potent human in vitro primary immune response.
Dendritic cells (DC) are the major APCs involved in naive T cell activation making them prime targets of vaccine research. We observed that mRNA was efficiently transfected, resulting in superior translation in DC compared with other professional APCs. A single stimulation of T cells by HIV gag-encoded mRNA-transfected DC in vitro resulted in primary CD4(+) and CD8(+) T cell immune responses at frequencies of Ag-specific cells (5-12.5%) similar to primary immune responses observed in vivo in murine models. Additionally, mRNA transfection also delivered a maturation signal to DC. Our results demonstrated that mRNA-mediated delivery of encoded Ag to DC induced potent primary T cell responses in vitro. mRNA transfection of DC, which mediated efficient delivery of antigenic peptides to MHC class I and II molecules, as well as delivering a maturation signal to DC, has the potential to be a potent and effective anti-HIV T cell-activating vaccine.
Antigen Presentation↗
A comparison of two methods of analog-to-digital medical video conversion.
The purpose of this study was to compare 2 methods of analog-to-digital video conversion in anticipation of improving, refining, and standardizing digital video production for medical education, diagnosis support, and telemedicine. A video workstation was devised containing 2 analog-to-digital video conversion systems: a digital video media converter with fire wire card and a video capture card. A procedure for final digital video production was created that used equivalent compression, pixel resolution, frame rate, and data rate for both systems. A subjective test was performed in which 12 archived analog videotapes, consisting of magnetic resonance angiograms, ultrasounds, neurosurgeries, and telemedicine applications, were converted digitally using the 2 methods. Randomized side by side video comparisons were analyzed and rated by subjective quality. An objective test was performed by videotaping a gray-scale test pattern off a computer monitor, digitally converting it by the 2 methods, and comparing the gray-scale values to the original pattern. There was no significant difference in overall video quality (P = .31) or grayscale reproduction using the 2 methods of analog-to-digital conversion. When performing simple analog-to-digital video conversion, a video capture card is equal in quality and costs less than a digital video (DV) media converter or fire wire card. If a digital video camera is available for use, then a DV media converter or fire wire card is more advantageous because it enables full operation of the digital video camera.
Analog-Digital Conversion↗
Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group.
CONTEXT: Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis (RA). OBJECTIVE: To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA. DESIGN: Randomized, double-blind, placebo, and active-controlled 12-month study. SETTING: Forty-seven university and private rheumatology practices in the United States and Canada. PATIENTS: Diagnosis of RA by the American College of Rheumatology (ACR) criteria for duration of 6 months or longer and no previous methotrexate treatment. INTERVENTION: Leflunomide treatment (20 mg/d), placebo, or methotrexate treatment (7.5-15 mg/wk). MAIN OUTCOME MEASURES: American College of Rheumatology success rate (completed 52 weeks of treatment and met the ACR > or = 20% response criteria), disease progression as assessed by x-ray films, and improvement in function and health-related quality of life using the intent-to-treat population. RESULTS: The 482 patients studied were predominantly women (mean age, 54 years; mean disease duration, 6.7 years) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P<.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P=.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P<.001 and P<.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy. CONCLUSIONS: Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life.
Adult↗
Substance P activates coincident NF-AT- and NF-kappa B-dependent adhesion molecule gene expression in microvascular endothelial cells through intracellular calcium mobilization.
Upon stimulation, cutaneous sensory nerves release neuropeptides such as substance P (SP), which modulate responses in the skin by activating a number of target cells via neurokinin receptors. We have demonstrated that SP preferentially binds to the NK-1R on human dermal microvascular cells, resulting in increased intracellular Ca2+ and induction of ICAM-1 and VCAM-1 expression. In the current studies, we identify specific elements in the regulatory regions of ICAM-1 and VCAM-1 genes as necessary and sufficient for SP-dependent transcriptional activation. SP treatment of human dermal microvascular endothelial cells leads to coincident activation and binding of the transcription factor NF-AT to the -191/-170 region of the ICAM-1 gene (a region bound by activated p65/p65 homodimers in response to TNF-alpha), and NF-kappa B (p65/p50) to tandem NF-kappa B binding sites at -76/-52 of the VCAM-1 gene. The SP-elicited intracellular Ca2+ signal was required for activation and subsequent binding of both NF-AT and NF-kappa B. The transacting factor induction by SP was specific, since a selective NK-1R antagonist blocked SP activation and subsequent NF-AT and NF-kappa B activation and binding. These data demonstrate coincident activation of NF-AT and NF-kappa B via SP-induced intracellular Ca2+ mobilization and indicate a crucial role for neuropeptides in modulating localized cutaneous inflammatory responses.
5' Untranslated Regions↗
Examination of the structure/function relationship in the exchangeable apolipoprotein, apolipophorin-III.
Exchangeable apolipoproteins are proteins that reversibly bind lipoprotein particles to facilitate their transport in vivo. The structure/function relationship of apolipophorin-III (apo-III), the only insect exchangeable apolipoprotein, has been investigated by examining the association of this protein with lipid vesicles. The importance of a conserved leucine residue, reported to be essential for apo-III binding to lipids, has been evaluated through site-directed mutagenesis. A unique cysteine replaces the conserved leucine at position 30 in recombinant apo-III (L30C protein). This substitution results in the covalent dimerization of the apo-III mutant via a disulfide bond. The cysteine mutation causes no difference in surface hydrophobicity of the L30C proteins when compared to the wild type apo-III. Wild type apo-III, L30C monomer, and L30C dimer associate with dimyristoylphosphatidylcholine (DMAC) vesicles in a similar manner, resulting in a reduction of turbidity of a phospholipid vesicle suspension. Analysis with transmission electron microscopy (TEM) reveals disk-like complexes identical to those previously reported with the wild type apo-III. Because the mutation of the conserved leucine seems to affect the solution behavior and surface hydrophobicity of apo-III, this residue is likely to be exposed to the aqueous environment. However, the similar behaviors of the wild type protein, the L30C monomer, and L30C dimer with respect to the binding of phospholipid vesicles suggest that this residue is not absolutely required for the protein binding to hydrophobic or amphiphilic interfaces.
Amino Acid Substitution↗
Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene.
Interleukin-18 is a potent inducer of interferon-gamma by activated T cells, macrophages, and monocytes and is synthesized as an inactive precursor. Pro-interleukin-18 must be cleaved by interleukin-1-beta-converting enzyme for secretion of the biologically active form. We report that among selected non-bone marrow derived skin cells, interleukin-18 mRNA is constitutively expressed by human keratinocytes and not by dermal microvascular endothelial cells, dermal fibroblasts, or melanocytes. Interleukin-18 mRNA and intracellular protein levels are neither changed in human keratinocytes nor induced in human dermal microvascular endothelial cells, dermal fibroblasts, or melanocytes by exposure to pro-inflammatory stimuli. Exposure of human keratinocytes to phorbol 12-myrisate 13-acetate, lipopolysaccharides or the contact sensitizer DNCB results in the secretion of immunoprecipitable interleukin-18 protein. Human keratinocyte-secreted interleukin-18 is biologically active, in that conditioned media from phorbol 12-myrisate 13-acetate, lipopolysaccharide and DNCB-treated human keratinocytes induce interferon-gamma expression by peripheral blood mononuclear cells. This bioactivity is neutralized by anti-interleukin-18, but not anti-interleukin-12 antibodies. By immunohistochemistry, interleukin-18 protein is detected in basal keratinocytes of normal human skin, but its expression is markedly upregulated in suprabasal keratinocytes in psoriasis. These findings indicate that human keratinocytes are a source of biologically functional interleukin-18 and thus are capable of playing an initiating part in the local interferon-gamma-dependent inflammatory processes through expression, activation, and secretion of interleukin-18.
Dinitrochlorobenzene↗
A molecular analysis of hyalin--a substrate for cell adhesion in the hyaline layer of the sea urchin embryo.
The hyaline layer of echinoderm embryos is an extraembryonic matrix that functions as a substrate for cell adhesion through early development. The major constituent of the hyaline layer is the protein hyalin, a fibrillar glycoprotein of approximately 330 kDa that multimerizes in the presence of calcium. Here we provide a molecular characterization of hyalin and identify a region of the protein that is important for its function in cell adhesion. Partial hyalin cDNAs were identified from two sea urchin species, Strongylocentrotus purpuratus and Lytechinus variegatus, by screening expression libraries with monoclonal antibodies to hyalin. The cDNAs each encode a tandemly arranged series of conserved repeats averaging 84 amino acids. These hyalin repeats are as similar between the two species as they are to repeats within each species, suggesting a strong functional conservation. Analysis of this repeat shows that it is a unique sequence within the GenBank database with only weak similarity to mucoid protein sequences. The hyalin mRNA is approximately 12 kb in length and is present in developing oocytes coincident with the appearance of cortical granules, the vesicle in which the hyalin protein is specifically packaged. The mRNA is present throughout oogenesis but is rapidly lost at oocyte maturation so that eggs and early embryos have no detectable hyalin mRNA. The hyalin protein, however, remains at relatively constant levels throughout development. Thus, all the hyalin protein present during early development, when no RNA is detectable, is maternally derived and exocytosed from cortical granules at fertilization. Hyalin mRNA reaccumulates in embryos beginning at the mesenchyme blastula stage; a RNA gel blot and in situ hybridization analysis of gastrulae and larvae shows a progressive confinement of hyalin mRNA to the aboral ectoderm. Recombinant hyalin containing the tandem repeat region of the protein was expressed in bacteria and is shown to serve as an adhesive substrate, almost equal to that of native hyalin, in cell adhesion assays. This adhesive activity is partially blocked by dilute hyalin monoclonal antibody Tg-HYL to the same extent as that for native hyalin. Thus, this hyalin repeat region appears to contain the ligand for the hyalin cell surface receptor. These data help explain some of the classic functions ascribed to the hyalin protein in early development and now enable investigators to focus on the mechanisms of cell interactions with the hyaline layer.
Amino Acid Sequence↗
pH responsive microdomain formation in a de novo polypeptide.
Recombinant DNA technology has been employed to produce a polypeptide capable of forming pH responsive hydrophobic microdomains. The design of this peptide is based upon an idealized conceptual model in which electrostatic, hydrophobic, and hydration forces are responsible for the association of amphipathic alpha-helical elements. Reduction in solution pH is responsible for reducing electrostatic repulsions between similarly charged residues, promoting the hydrophobic collapse of helical elements. A polymerizable synthetic element (dn31) has been synthesized and inserted into an appropriate expression vector. A clone containing a single copy of the dn31 gene (designated dn3lx1) was isolated and the corresponding gene product DN3Lx1 isolated. The physical properties of DN3Lx1 were examined in solution by gel filtration chromatography. CD, and fluorescence probe analysis. It was determined that DN3Lx1 self-associates in solution with the degree of aggregation dependent on pH and ionic strength. An initial objective of this work was to examine domain organization in higher molecular weight species containing ten or more repetitive sequences. However, attempts to express multiple repeats of DN3Lxn from concatemers were unsuccessful.
Amino Acid Sequence↗
The association among gastric mucosal pH, endotoxemia, and low systemic vascular resistance after cardiopulmonary bypass.
OBJECTIVE: Previously, it was found that a number of patients suffer a "low systemic vascular resistance syndrome" after cardiopulmonary bypass, and this was hypothesized to be secondary to endotoxemia, resulting from intestinal ischemia during bypass. DESIGN: Prospective cohort. SETTING: University teaching hospital. PARTICIPANTS: Thirty-two patients undergoing cardiac surgery. INTERVENTIONS: A number of variables relating to adequacy of tissue perfusion were measured at seven time periods perioperatively: cardiac output, systemic vascular resistance, oxygen delivery and consumption, oxygen extraction ratio, gastric mucosal pH, serum lactate, and endotoxin levels. MEASUREMENTS AND MAIN RESULTS: Investigators could not find any association between systemic vascular resistance and mucosal pH or endotoxin levels after bypass. There were significant changes in oxygen flux and extraction ratio (p < 0.001) as well as serum lactate (p < 0.001). There was no significant change in endotoxin levels or mucosal pH. The systemic vascular resistance at 6 hours postbypass could be predicted from the vascular resistance reading at 1 hour postbypass by a regression equation. A significant correlation between systemic vascular resistance and mixed venous oxygen was found at 4 and 6 hours postbypass (p < 0.01) as well as with oxygen extraction (p < 0.01). There was a negative correlation between mucosal pH and serum lactate, particularly at 6 hours postbypass (p < 0.01). There was no correlation between mucosal pH and endotoxin levels, oxygen flux, or cardiac output. CONCLUSIONS: The investigators therefore could not find any evidence that intestinal ischemia during bypass, as measured by gastric mucosal pH, predisposes to endotoxemia, or low systemic vascular resistance after cardiac surgery.
Adult↗
[An analysis of the recommendations on sugar consumption p between 1961 and 1991].
It is study made an analysis of national expert reports on dietary guidelines published all over the world in the 30-year period between 1961 and 1991. The aim is to identify what the reports recommend about the consumption of sugars and their relation to chronic diseases, and also what advice should be given to the public and appropriate authorities regarding levels of sugars in the diet. Information was gathered from 115 reports published by experts committees in 36 different countries and regions of the world, including developed and developing countries. The results showed that the great majority (84.5%) of the reports analysed make recommendations on the extrinsic consumption of sugar and that there is an agreement that these sugars, especially sucrose, must be reduced in the diet. The commonest level proposed is that 10% of total calorie intake from extrinsic sugars should be considered the maximum level. Such advice is often addressed to the general population and it is offered with a view to the maintenance of general health and especially to the prevention dental caries and obesity. It was concluded that advice on the intake of sugars given by dietary guidelines in the last three decades is coherent with the existing scientific evidence on the relationship between sugars and human diseases and, therefore, they should be integrated into national food and health policies.
Dental Caries↗
Nucleic acid sequence analysis software for microcomputers.
It is clear that a computer-aided data control system is required for even small laboratories generating nucleic acid data. While the molecular biologist at many universities and large research institutions has access to mainframe computers and nucleic acid sequence analysis software, many find it more convenient to perform sequence analysis on microcomputers that are typically located within the investigator's laboratory and totally dedicated to sequence storage and analysis, in essence giving the investigator more personal control of analysis activities than is sometimes possible with shared mini- or mainframe computers. New programs are being written and released at an increasing rate to perform increasingly more complex and specialized analyses using small computer-based systems. This trend will undoubtedly continue, fueled by the need to manage the ever increasing quantity of sequence data.
Base Sequence↗
Induction of B-cell lymphomas in athymic NIH Swiss nu/nu mice.
A B-cell lymphoma was induced in athymic NIH Swiss nu/nu mice by challenging the animals with NIH3T3 cells, previously transfected with a recombinant DNA carrying a human oncogene hhcM, ligated to an SV40 promoter with a neomycin-resistance marker. The gross pathology of the tumor-bearing animal revealed generalized lymphadenopathy and the histopathology indicated widespread infiltration of lymphocytes into organs, such as brain, liver, kidney and lung, in addition to the lymphoid tissues and spleen; the appearance was consistent with diffuse histiocytic lymphoma. Direct immunofluorescence assays with specific typing anti-sera on live cells prepared from spleen and various lymph nodes in short-term culture, suggested the cells were B-cells. This B-cell lymphoma provides an experimental model, not only for studying possible oncogene activation but also for studying the various interactions involved in signal transduction essential for the activation of B-cell proliferation and differentiation.
Animals↗
British Nutrition Foundation.
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Food Supply↗