158 research outputs found
Sensitive Solid-Phase Detection of Donor-Specific Antibodies as an Aid Highly Relevant to Improving Allograft Outcomes
No full textTransplant recipients who have had sensitizing events such as pregnancies, blood transfusions and previous transplants often develop antibodies directed against human leukocyte antigen (HLA)-molecules of the donor tissue. These pre-formed donor-specific antibodies (DSA) represent a high risk of organ failure as a consequence of antibody-mediated hyper-acute or acute allograft rejection. As a first assay to detect DSA, the complement-dependent lymphocytotoxicity assay (CDC) was established more than 40 years ago. However, this assay is characterized by several drawbacks such as a low sensitivity and a high susceptibility to various artificial factors generally not leading to valid and reliable outcomes under several circumstances that are reviewed in this article. Furthermore, only those antibodies that exert complement-fixing activity are detected. As a consequence, novel procedures that act independently of the complement system and that do not represent functional assays were generated in the format of solid phase assays (SPAs) (bead- or ELISA-based). In this article, we review the pros and cons of these sensitive SPA in comparison with the detection of DSA through the use of the traditional methods such as CDC and flow cytometric analyses. Potential drawbacks of the alternative methodological approaches comprising high background reactivity, susceptibility to environmental factors and the possible influence of subjective operators' errors concerning the interpretation of the results are summarized and critically discussed for each method. We provide a forecast on the future role of SPAs reliably excluding highly deleterious DSA, thus leading to an improved graft survival
Cytokine-inducible CD40 expression in human endothelial cells is mediated by interferon regulatory factor-1
No full textGiven the significance of CD40-CD40 ligand interactions in chronic inflammatory diseases including atherosclerosis, the transcriptional regulation of CD40 expression as a potential therapeutic target was investigated in human umbilical vein cultured endothelial cells. Exposure to interferon-gamma (IFN-gamma) plus tumor necrosis factor-a resulted in a marked synergistic de novo expression of CD40, which, according to electrophoretic mobility shift analysis, was attributable to activation of the transcription factors nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription-1 (STAT-1), and interferon regulatory factor-1 (IRF-1). Subsequent time-course studies revealed that de novo synthesis of IRF-1 preceded that of CD40. Decoy oligodeoxynucleotide (ODN) neutralization of STAT-1 or IRF-1, but not of NF-kappaB, inhibited cytokine-stimulated CD40 expression by 60% at both the mRNA and protein levels, and this effect was mimicked by antisense ODN blockade of IRF-1 synthesis. In contrast, CD40 expression in response to IFN-gamma stimulation was sensitive to neutralization of STAT-1 only. These findings suggest that depending on the cytokine composition, CD40 expression In human endothelial cells under proinflammatory conditions Is governed by STAT-1 either directly or Indirectly through de novo synthesis of IRF-1. Moreover, decoy ODN neutralization of these transcription factors may provide a novel therapeutic option for Interfering with CD40-CD40 ligand-mediated Inflammatory responses in vivo. (Blood. 2002;99:520-525) (C) 2002 by The American Society of Hematology
Dynamics of Protein Kinase C-mediated Phosphorylation of the Complement C5a Receptor on Serine 334
No full textUpon agonist binding, the C5a anaphylatoxin receptor (C5aR) is rapidly phosphorylated on phosphorylation sites that are located within the C-terminal domain of the receptor. Previous studies suggested that C5aR phosphorylation proceeds in a hierarchical manner with serine 334 presenting a highly accessible priming site that controls subsequent phosphorylation at other positions. To better understand the dynamics of Ser-334 phosphorylation, we generated site-specific monoclonal antibodies that specifically react with phosphoserine 334. In differentiated U937 cells, which endogenously express C5aR, stimulation with low C5a concentrations resulted in a very rapid (t2/1 similar to 20 s), albeit transient, receptor phosphorylation. Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of Ser-334 is regulated by protein kinase C-beta and a calyculin A-sensitive protein phosphatase. Surprisingly, at high concentrations (> 10 nM) of C5a, the protein kinase C-mediated phosphorylation of Ser-334 was essentially blocked. This could be attributed to the even faster (t2/1 < 5 s) binding of beta-arrestin to the receptor. Analysis of C5aR Ser/Ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of C-terminal phosphorylation sites since all 4 serine residues could individually support C5aR internalization and desensitization. This study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a G protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation
A Case Report and Review of the Literature: Reactive Arthritis Caused by Clostridioides difficile ribotype 027
No full textWith an annual incidence of 250-300 per 100,000 inhabitants, reactive arthritis is not uncommon. However, the fact that Clostridioides difficile infection (CDI) can also lead to this complication is largely unknown. We report on a 69-years-old man who developed reactive arthritis of his right knee joint one week after antibiotic-associated diarrhea with evidence of C. difficile of the hypervirulent ribotype 027. His female partner also became infected with C. difficile ribotype 027, but did not develop reactive arthritis. The further investigation showed that the patient - in contrast to his partner - was HLA-B27 positive and had strong antibody levels against C. difficile . The case history together with the review of 45 other cases described so far shows that C. difficile can also lead to reactive arthritis. C. difficile -associated reactive arthritis (CDARA) is characterized by the fact that patients suffer from diarrhea or colitis after taking antibiotics, toxigenic C. difficile or only the toxins are detectable in the stool and there are no other explanations for the arthritis and diarrhea.Niedersächsische Ministerium für Wissenschaft und KulturOpen-Access-Publikationsfonds 202
Metabolomic Profiling in Patients with Different Hemodynamic Subtypes of Severe Aortic Valve Stenosis
No full textSevere aortic stenosis (AS) is a common pathological condition in an ageing population imposing significant morbidity and mortality. Based on distinct hemodynamic features, i.e., ejection fraction (EF), transvalvular gradient and stroke volume, four different AS subtypes can be distinguished: (i) normal EF and high gradient, (ii) reduced EF and high gradient, (iii) reduced EF and low gradient, and (iv) normal EF and low gradient. These subtypes differ with respect to pathophysiological mechanisms, cardiac remodeling, and prognosis. However, little is known about metabolic changes in these different hemodynamic conditions of AS. Thus, we carried out metabolomic analyses in serum samples of 40 AS patients (n = 10 per subtype) and 10 healthy blood donors (controls) using ultrahigh-performance liquid chromatography–tandem mass spectroscopy. A total of 1293 biochemicals could be identified. Principal component analysis revealed different metabolic profiles in all of the subgroups of AS (All-AS) vs. controls. Out of the determined biochemicals, 48% (n = 620) were altered in All-AS vs. controls (p < 0.05). In this regard, levels of various acylcarnitines (e.g., myristoylcarnitine, fold-change 1.85, p < 0.05), ketone bodies (e.g., 3-hydroxybutyrate, fold-change 11.14, p < 0.05) as well as sugar metabolites (e.g., glucose, fold-change 1.22, p < 0.05) were predominantly increased, whereas amino acids (e.g., leucine, fold-change 0.8, p < 0.05) were mainly reduced in All-AS. Interestingly, these changes appeared to be consistent amongst all AS subtypes. Distinct differences between AS subtypes were found for metabolites belonging to hemoglobin metabolism, diacylglycerols, and dihydrosphingomyelins. These findings indicate that relevant changes in substrate utilization appear to be consistent for different hemodynamic subtypes of AS and may therefore reflect common mechanisms during AS-induced heart failure. Additionally, distinct metabolites could be identified to significantly differ between certain AS subtypes. Future studies need to define their pathophysiological implications
The Tale of Johnny Town-Mouse
No full textSee my notes on the 1918/87 version. This book has a slightly different cover and dust jacket, and does not proclaim the original and authorized edition or new colour reproductions, as does the 1987 reprint. In fact, the illustrations here are less distinct.This is a hardbound book (hard cover)Beatrix Potte
Beatrix Potter Through the Years
No full textThe investigation into the life and work of Beatrix Potter was prompted by interest in and enjoyment of the work of this author. The Tale of Peter Rabbit was the real extent of the acquaintance with Beatrix Potter. Perhaps the appreciation of the art in this book was even more fundamental. A serious desire for children to be familiar with the original story rather than the reproductions was a factor in wanting to know more about this woman and more about what she had produced
The Picture Letters: an "Illustrated Story-Telling" by Beatrix Potter
No full textA distinctive and noteworthy detail of Beatrix Potter’s literary production is her ability to coordinate text and illustrations, both created by herself. This feature is already evident in the picture letters that the author addressed to children and acquaintances, and that will inspire her most famous stories.
In my presentation, I focus primarily on Beatrix Potter’s artistic education. Then I dwell the characteristics of her picture letters, making particular reference to the evolution of the Tale of Peter Rabbit from letter to its first commercial edition. Finally, as illustrations are so important in Beatrix Potter’s picture letters as well as in her later books, I focus on their characteristics, emphasizing their innovations compared to other children’s illustrations of her age.Even as a child, Beatrix Potter (1866-1943) shows a strong propensity for the arts. Grown up studying scientific manuals, didactic tales, and picture books for children, and observing with curiosity the world around her, Beatrix Potter in her literary production combines the talent for prose with that for drawing. In fact, in the many tales for which she is remembered, many illustrations are used as a supplement to the written text.
The interesting relationship between text and images is particularly evident demonstrated in the series of picture letters – an expression coined by the author herself – letters that Beatrix Potter directs to the Moore children, and from which she will draw inspiration for her most famous characters, such as Peter Rabbit and Benjamin.
In my paper, I intend to study this series of letter, dwelling in particular on their format, based on the relationship between narration and pictures. This formal choice is a true artistic statement of the author, a choice that offers multiple interpretations to the story, and stimulates the attention of the children to whom the letters are addressed, realizing what Linda Lear defines as an “illustrated story-telling”.
Thanks to their unconventional format, the picture letters represent a focal point in Beatrix Potter’s literary production. Probably, just understanding how much her young readers appreciated these letters, the author reached to the idea of writing and illustrating books for children.
These letters are also an artistic experiment and a valid means to mediate between contrasting worlds: the imagination and the natural sciences, fantastic stories for children and the social considerations Beatrix Potter provides in her diary, the iconic impact of the visual set against the structural elements at the base of story-telling (Lear, 2008:132). Nor should it be forgotten that Beatrix Potter used her real life and pets as inspiration for her picture letters. Thus, the letters are capable of reconciling the author’s private experience and her public art.
Illustrations in the picture letters deserve particular attention. They are inspired by the pictures drawn by famous artists for children, such as Edward Lear (1812-1888), Walter Crane (1845-1915), and Rudolph Caldecott (1846-1886). At the same time, Beatrix Potter demonstrates an exceptional scientific accuracy and invaluable attention to detail in them. The self-apprenticeship and study Beatrix Potter had pursued at the Natural History Museum in South Kensington strongly influences the animals in the picture letters – even if they are anthropomorphized, as evidenced by the pretty clothes with which they are equipped – and the bucolic nature around them. The scientific attention demonstrated by Potter’s pictures testifies to a well-spread Victorian attention for the natural sciences, displayed especially by high-society women
Genetic control of the alternative pathway of complement in humans and age-related macular degeneration
No full textActivation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues.NEI NIH HHS [EY014467
Jeszcze o "Beatrix Cenci" Juliusza Słowackiego
No full textHanna Sieja-Skrzypulec makes a comparative interpretation of the drama and its Kraków staging from 2009 directed by Maciej Sobociński (a premiere in The Juliusz Słowacki Theatre) making the notions of re-creation and repetition, as well as a teatrum mundi topos the key words. The author points to a consciously emphasized “mirror” structure of drama in staging, reinforced on the stage by multimedia. The text concentrates on the image (face) of Beatrix (painting reproductions, movies, theatrical staging), hence her identity and dignity had to be defended in the patriarchal world.Hanna Sieja-Skrzypulec makes a comparative interpretation of the drama and its Kraków staging from 2009 directed by Maciej Sobociński (a premiere in The Juliusz Słowacki Theatre) making the notions of re-creation and repetition, as well as a teatrum mundi topos the key words. The author points to a consciously emphasized “mirror” structure of drama in staging, reinforced on the stage by multimedia. The text concentrates on the image (face) of Beatrix (painting reproductions, movies, theatrical staging), hence her identity and dignity had to be defended in the patriarchal world
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