Images in cardiovascular medicine. Giant left ventricular pseudoaneurysm.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
M O'Reilly
Publications and source records attributed to M O'Reilly.
Antiangiogenic therapy of transgenic mice impairs de novo tumor growth.
Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycline, and interferon alpha/beta. The treatment regimen markedly attenuated tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The proliferation index of tumor cells in treated and control mice was similar, whereas the apoptotic index was doubled in treated tumors. This study shows that de novo tumor progression can be restricted solely by antiangiogenic therapy. The results suggest that angiogenesis inhibitors represent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangiogenic agents.
Adenoma, Islet Cell↗
Radiological case of the month. Psoas pyomyositis.
Explore the source record for details and available documents.
Child↗
Control by phosphorylation.
The two examples of phospho and dephospho proteins for which structural data were previously available (glycogen phosphorylase and isocitrate dehydrogenase) demonstrated two different mechanisms for control. In glycogen phosphorylase, activation by phosphorylation results in long-range allosteric changes. In isocitrate dehydrogenase, inhibition by phosphorylation is achieved by an electrostatic blocking mechanism with no conformational changes. During the past year, the structures of the phospho and dephospho forms of two more proteins, the cell cycle protein kinase CDK2 and yeast glycogen phosphorylase, have been determined. The new results highlight the importance of the phosphoamino acids both in the organization of local regions of protein structure through phosphate-arginine interactions and in the promotion of long-range conformational responses.
Binding Sites↗
Metazoan rDNA enhancer acts by making more genes transcriptionally active.
Enhancers could, in principle, function by increasing the rate of reinitiation on individual adjacent active promoters or by increasing the probability that an adjacent promoter is activated for transcription. We have addressed this issue for the repetitive metazoan rDNA enhancer by microinjecting Xenopus oocytes with enhancer-less and enhancer-bearing genes and determining by EM the frequency that each gene type forms active transcription units and their transcript density. We use conditions where transcription requires the normal rDNA promoter and is stimulated 30-50-fold by the enhancer. (In contrast, at saturating template conditions as used in previous EM studies, an aberrant mode of transcription is activated that is not affected by the rDNA enhancer or by the generally recognized rDNA promoter). The active transcription units on enhancer-less genes are found to be as densely packed with nascent transcripts and polymerases as those on enhancer-bearing genes and on the endogenous rRNA genes. Significantly, the enhancer-bearing genes are approximately 30-50-fold more likely to form such active transcription units than enhancer-less genes, consistent with their amounts of transcript. Complementary studies confirm that the enhancer does not affect elongation rate, the stability of the transcription complex, or transcript half-life. These data demonstrate that the repetitive metazoan rDNA enhancer causes more genes to be actively transcribed and does not alter the reinitiation rate on individual active genes.
Animals↗
The scintigraphic features of giant-cell tumors in relation to other imaging modalities.
Thirty-three patients with untreated giant-cell tumors of bone were studied with Tc-99m phosphate scintigraphy. The scintigraphic patterns of the tumors were varied and the tumors exhibited extended uptake of radioactivity in the majority of cases. The homogeneously diffuse pattern and the nonhomogeneous "doughnut" and "blob" patterns are described. The scintigraphic patterns of giant-cell tumors are considered in the light of the radiographic, angiographic, CT, and MR imaging studies and the histopathologic findings.
Adolescent↗
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances pulmonary defenses against pneumococcal infections after splenectomy.
BACKGROUND: Splenectomized individuals are at risk for pneumococcal sepsis. Alveolar macrophage bactericidal function is depressed after splenectomy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has pronounced effects on the number and function of macrophages. We hypothesized that GM-CSF treatment could improve alveolar macrophage bactericidal activity against pneumococci, and improve survival with pneumococcal infection. METHODS: Two weeks after splenectomy or sham operation, mice were treated with GM-CSF or saline twice daily for varying times. Alveolar macrophages were obtained by bronchopulmonary lavage, and bactericidal activity was measured. Survival was assessed after pneumococcal aerosol challenge. RESULTS: Alveolar macrophage bactericidal activity was improved with GM-CSF treatment in both eusplenic and asplenic mice (p < 0.001). GM-CSF treatment improved survival in both groups (p < 0.001). CONCLUSIONS: GM-CSF can augment alveolar macrophage function and provide protection against pneumococcal infections. It may be a useful adjuvant therapy for normal and splenectomized individuals.
Animals↗
The phage-like element PBSX and part of the skin element, which are resident at different locations on the Bacillus subtilis chromosome, are highly homologous.
PBSX and skin are two unusual genetic elements resident on the Bacillus subtilis chromosome. PBSX is a phage-like element located at approximately 100 degrees which is induced by the SOS response and results in cell lysis with the release of phage-like particles. The phage particles contain bacterial chromosomal DNA and kill sensitive bacteria without injecting DNA. The skin element is located at approximately 230 degrees on the chromosome and is positioned within the sigK open reading frame (ORF). It is excised at a particular stage of sporulation, leading to reconstitution of the complete sigK gene. In this paper, we show that there are phage-like operons present in the skin element which are highly homologous to the region of PBSX comprising part of the control region and the late operon. These operons are similar in terms of their gene organization, the percentage identity of the products of homologous ORFs and the positioning and strengths of ribosome-binding sites for each ORF. Although this high degree of conservation suggests that the phange-like operons in skin can be expressed, expression of the late operon was not detected during exponential growth, during sporulation or after induction of the SOS response. However two non-phage-like operons in the skin element are expressed and have distinct expression profiles that are dependent on the growth and developmental status of the cell.
Bacillus Phages↗
Modifying the host response to injury. The future of trauma care.
It is beyond the scope of this article to describe all of the contributions of molecular biology to increasing our understanding of the pathophysiology of inflammation and the response to injury. This review focuses on those aspects that are clinically relevant. In addition to providing quantities of recombinant proteins, recent advances in molecular and cellular biology have provided other tools to help differentiate the pathophysiology of the host response to injury and infection. Hybridoma technology has facilitated the development of specific antibodies that are used to block the activity of a specific factor or toxin. Receptor and signal transduction biology has provided further insight into the activity and function of various factors and mediators. Studies at the level of the gene have shed light on the phylogenic relationship among various factors. Transgenic animals can be used to determine the effects of excess factor production; conversely, genetic "knockouts" are useful in determining the pathophysiology associated with the absence of a particular factor. It is clear that as our understanding of the complex interactions leading to inflammation increases, we will be able to take advantage of this knowledge to more effectively treat patients.
Cytokines↗
The reliability of upper airway landmark identification.
Research involving the upper airway has assessed linear measurements of certain structures on the assumption that the landmarks involved can be reliably identified. This study was conducted to determine the reliability of landmark identification for those structures most commonly reported in the obstructive sleep apnoea literature. Three judges were asked to identify specific landmarks on 20 randomly selected radiographs and 10 superior quality radiographs. This was repeated one week later. The results of the analysis of variance (ANOVA) indicated that the majority of the landmarks could be reliably identified, irrespective of the quality of the radiograph. However, the quality of the radiograph did affect identification of the horizontal position of the hyoid bone and the linear measure of posterior airway space although these were not clinically significant. The vertical position of the tip of the soft palate was highly unreliable, irrespective of the quality of the radiograph. This resulted in errors in the measurement of soft palate length. Future airway-related research should consider the potential inaccuracies when attempting to identify these dynamic three-dimensional structures on static two-dimensional images.
Analysis of Variance↗
Dose dependency of granulocyte-macrophage colony stimulating factor for improving survival following burn wound infection.
Infections remain a serious problem following injury. Immune modulation offers an additional strategy for the treatment of infections. We evaluated the ability of a multilineage hematopoietic growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), to improve survival following burn injury with a superimposed burn wound infection. Groups of 12 BDF1 mice received a 15% total body surface area (TBSA) thermal injury by immersion in 100 degrees C water; 6 x 10(3) Pseudomonas was then applied to the burn wound. The GM-CSF was injected subcutaneously B.I.D. for 7 days. Mice receiving the 10-ng dose of GM-CSF had significantly improved survival compared with the controls; other doses had no significant effect on survival. Clinical trials to assess the ability of GM-CSF to reduce infectious complications following burn injury are underway and these data suggest selecting a specific dose may be critical in achieving maximal benefit.
Animals↗
Augmentation of alveolar macrophage phagocytic activity by granulocyte colony stimulating factor and interleukin-1: influence of splenectomy.
The use of cytokines and other naturally occurring substances as biopharmaceuticals for modulating the host response to trauma and infection offers new therapeutic possibilities. Cytokine pretreatment protects animals in a variety of experimental models, including splenectomized mice following pneumococcal aerosol challenge. Since splenectomy appears to affect alveolar macrophage function, we postulated that pretreatment with interleukin 1 (IL-1) and granulocyte colony stimulating factor (G-CSF) improved survival in mice following aerosol challenge of live pneumococci by activating alveolar macrophages. Alveolar macrophage bactericidal and phagocytic function was slightly, but consistently, depressed following splenectomy. Interleukin-1 and G-CSF pretreatment had pronounced effects on macrophage phagocytic and bactericidal activity, and these effects were quite different depending upon whether the mice were eusplenic or asplenic. Splenectomy augmented the effects of IL-1 on alveolar macrophage bactericidal function compared with eusplenic mice (p < 0.001), while more pronounced effects on macrophage function following G-CSF treatment were seen in mice with intact spleens (p < 0.001). The use of cytokines and other substances to modify the host response to infection has great potential. Individuals with deficits such as splenectomy will have a different net response to therapy. It is important that we be able to predict these responses accurately in most patients in order to use these substances more effectively.
Animals↗
Sequence and analysis of the citrulline biosynthetic operon argC-F from Bacillus subtilis.
The citrulline biosynthetic operon argC-F located at 100 degrees on the Bacillus subtilis chromosome contains seven open reading frames which encode all the enzymes required for the biosynthesis of citrulline. The operon is transcribed as a single transcription unit. The second cistron of the operon is homologous to ArgJ (ornithine acetyltransferase) from Bacillus stearothermophilus and Neisseria gonorrhoeae, suggesting that the acetylation of glutamate and the deacetylation of acetylornithine are carried out by a single enzyme in a cyclical pathway. The argF gene is an orthologue of argF from Pseudomonas aeruginosa and a paralogue of arcB from P. aeruginosa and argF/argI from Escherichia coli.
Amino Acid Sequence↗
The citrulline biosynthetic operon, argC-F, and a ribose transport operon, rbs, from Bacillus subtilis are negatively regulated by Spo0A.
A method is described here that can be used to identify operons whose expression is controlled by any particular regulator protein. This method was used to identify operons whose expression is negatively regulated by Spo0A in Bacillus subtilis. Twenty-eight strains were identified, each of which contains an operon-lacZ transcriptional fusion, negatively regulated, either directly or indirectly, by Spo0A. In one of these strains (CSA8), the lacZ gene is fused to the argC-F operon positioned at 100 degrees on the B. subtilis chromosome. The regulated expression of this operon by Spo0A-P is mediated indirectly through the transition state regulator AbrB and is manifest only during growth on solid medium. In a second strain (CSA15), the lacZ gene is fused to an operon encoding a transport system which displays features characteristic of the ABC group of transporters, and which has a very high level of identity to the ribose transport system from Escherichia coli. Expression of the ribose transport operon is directed by a single SigA-type promoter. Transcription from this promoter is repressed by the phosphorylated form of Spo0A during the late-exponential/transition phase of the growth cycle and this control is not mediated through the transition-state regulator, AbrB.
Arginine↗
Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion.
Mouse skin carcinomas arise from a small subpopulation of benign papillomas with an increased risk of malignant conversion. These papillomas arise with limited stimulation by tumor promoters, appear rapidly, and do not regress, suggesting that they differ in growth properties from the majority of benign tumors. The transforming growth factor beta (TGF-beta) proteins are expressed in the epidermis and are growth inhibitors for mouse keratinocytes in vitro; altered TGF-beta expression could influence the growth properties of high-risk papillomas. Normal epidermis, tumor promoter-treated epidermis, and skin papillomas at low risk for malignant conversion express TGF-beta 1 in the basal cell compartment and TGF-beta 2 in the suprabasal strata. In low-risk tumors, 90% of the proliferating cells are confined to the basal compartment. In contrast, the majority of high-risk papillomas are devoid of both TGF-beta 1 and TGF-beta 2 as soon as they arise; these tumors have up to 40% of the proliferating cells in the suprabasal layers. Squamous cell carcinomas are also devoid of TGF-beta, suggesting that they arise from the TGF-beta-deficient high-risk papillomas. In some high-risk papillomas, TGF-beta 1 loss can occur first and correlates with basal cell hyperproliferation, while TGF-beta 2 loss correlates with suprabasal hyperproliferation. Similarly, TGF-beta 1-null transgenic mice, which express wild-type levels of TGF-beta 2 in epidermis but no TGF-beta 1 in the basal layer, have a hyperproliferative basal cell layer without suprabasal proliferation. In tumors, loss of TGF-beta is controlled at the posttranscriptional level and is associated with expression of keratin 13, a documented marker of malignant progression. These results show that TGF-beta expression and function are compartmentalized in epidermis and epidermal tumors and that loss of TGF-beta is an early, biologically relevant risk factor for malignant progression.
Animals↗
The terminal balls characteristic of eukaryotic rRNA transcription units in chromatin spreads are rRNA processing complexes.
When spread chromatin is visualized by electron microscopy, active rRNA genes have a characteristic Christmas tree appearance: From a DNA "trunk" extend closely packed "branches" of nascent transcripts whose ends are decorated with terminal "balls." These terminal balls have been known for more than two decades, are shown in most biology textbooks, and are reported in hundreds of papers, yet their nature has remained elusive. Here, we show that a rRNA-processing signal in the 5'-external transcribed spacer (ETS) of the Xenopus laevis ribosomal primary transcript forms a large, processing-related complex with factors of the Xenopus oocyte, analogous to 5' ETS processing complexes found in other vertebrate cell types. Using mutant rRNA genes, we find that the same rRNA residues are required for this biochemically defined complex formation and for terminal ball formation, analyzed electron microscopically after injection of these cloned genes into Xenopus oocytes. This, plus other presented evidence, implies that rRNA terminal balls in Xenopus, and by inference, also in the multitude of other species where they have been observed, are the ultrastructural visualization of an evolutionarily conserved 5' ETS processing complex that forms on the nascent rRNA.
Animals↗
The K88 fimbrial adhesin of enterotoxigenic Escherichia coli binds to beta 1-linked galactosyl residues in glycosphingolipids.
The K88 fimbrial adhesin enables certain strains of enterotoxigenic Escherichia coli to adhere to the porcine small intestine. In this study, the ability of the K88 adhesin to bind to glycosphingolipids was monitored by modified enzyme-linked immunosorbent assay and thin-layer chromatography overlay binding analysis. The binding of the K88 adhesin to glycosphingolipid-coated microtiter plates was saturable, with 50% maximal binding occurring with gangliotriaosylceramide, gangliotetraosylceramide, and lactosylceramide at 67 +/- 21, 117 +/- 21, and 73 +/- 22 pM, respectively. Thin-layer chromatography overlay binding analysis demonstrated that serotype O8:K87:K88ab:H19 E. coli bound to hydroxylated galactosylceramide, gangliotriaocylceramide, gangliotetraosylceramide, and lactosylceramide but not to globotriaosylceramide, nonhydroxylated galactosylceramide, glucosides, glucosylceramide, or a mixture of ceramides. The K88 adhesin did not bind by either assay to globoside, the Forssman glycolipid, GM1, GM2, GM3, GD1a, GD2, GD3, GQ1b, or GT1b. The binding pattern observed with the K88 adhesin suggests that beta 1-linked galactosyl residues are the minimum determinant required for binding, provided they are presented correctly. It is suggested that beta 1-linked galactose residues may form the molecular basis of both glycoprotein and glycolipid receptors for the K88 fimbrial adhesin in the porcine small intestine.
Adhesins, Escherichia coli↗
Metaphyseal abnormalities in fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is a rare, congenital disorder characterized by diffuse ossification of extraskeletal connective tissue. The classical features and progression of the disease are described and three cases are presented which fall into the general pattern of FOP clinically and radiologically. A constant feature seen was a slight metaphyseal flaring with spiking at the edges of the metaphyses, compatible with minor alteration in bone morphology during growth. These changes cannot be seen after epiphyseal fusion. The major abnormalities persist into adult life.
Bone and Bones↗