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Relevant bibliographies by topics / Gamma -heavy chain disease

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Academic literature on the topic 'Gamma -heavy chain disease'

Author: Grafiati

Published: 4 June 2021

Last updated: 14 February 2022

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Journal articles on the topic "Gamma -heavy chain disease"

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Bieliauskas, Shannon, Raymond R. Tubbs, Chris M. Bacon, Camellia Eshoa, Kathryn Foucar, Sarah E. Gibson, Steven H. Kroft, Aliyah R. Sohani, Steven H. Swerdlow, and James R. Cook. "Gamma Heavy-chain Disease." American Journal of Surgical Pathology 36, no. 4 (April 2012): 534–43. http://dx.doi.org/10.1097/pas.0b013e318240590a.

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Kušnierová, Pavlína, David Zeman, Tomáš Jelínek, and Roman Hájek. "Gamma-heavy chain disease." Klinicka Onkologie 33, no. 4 (August 15, 2020): 282–85. http://dx.doi.org/10.14735/amko2020282.

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FERMAND, JEAN-PAUL, JEAN-CLAUDE BROUET, FRANÇOISE DANON, and MAXIME SELIGMANN. "Gamma Heavy Chain “Disease”." Medicine 68, no. 6 (November 1989): 321–35. http://dx.doi.org/10.1097/00005792-198911000-00001.

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Westin, Jan, Raili Eyrich, Enevold Falsen, Leif Lindholm, Per Lundin, Ivar Lönnroth, and Aleksander Weinfeld. "GAMMA HEAVY CHAIN DISEASE." Acta Medica Scandinavica 192, no. 1-6 (April 24, 2009): 281–92. http://dx.doi.org/10.1111/j.0954-6820.1972.tb04817.x.

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Kanoh, Tadashi, and Hideo Nakasato. "Osteolytic gamma heavy chain disease." European Journal of Haematology 39, no. 1 (April 24, 2009): 60–65. http://dx.doi.org/10.1111/j.1600-0609.1987.tb00165.x.

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Kanoh, T. "Cutaneous lesions in gamma heavy-chain disease." Archives of Dermatology 124, no. 10 (October 1, 1988): 1538–40. http://dx.doi.org/10.1001/archderm.124.10.1538.

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Dickson, John R., Manfred Harth, David A. Bell, Ronald Komar, and William B. Chodirker. "Gamma heavy chain disease and rheumatoid arthritis." Seminars in Arthritis and Rheumatism 18, no. 4 (May 1989): 247–51. http://dx.doi.org/10.1016/0049-0172(89)90045-0.

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Pontet, F., X. Gué, C. Dosquet, J. Caen, and F. Rousselet. "Rapid evolution in the immunochemical findings of a gamma heavy chain disease." Clinical Chemistry 34, no. 2 (February 1, 1988): 439–43. http://dx.doi.org/10.1093/clinchem/34.2.439.

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Abstract We noted the following major immunochemical changes in the final course of a gamma heavy-chain disease associated with a myelomonocytic leukemia: an important oligoclonal increase of IgG1/kappa, during sepsis development, whereas the lambda molecules decreased and IgG2 and IgG3 completely disappeared in a one-month interval. Initial concentrations of IgG4 were stable during that period, and gamma 1 heavy chains were slightly increased. This is a very unusual observation of the successive immunochemical events terminating a gamma heavy-chain disease.

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Lassoued, Kais, Catherine Picard, Françoise Danon, Marianne Pocidalo, Maggy Grossin, Béatrice Crickx, and Stéphane Beiaich. "Cutaneous manifestations associated with gamma heavy chain disease." Journal of the American Academy of Dermatology 23, no. 5 (November 1990): 988–91. http://dx.doi.org/10.1016/s0190-9622(08)80110-7.

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Castelino, Daniel, Faye Gray, Anthony D’Apice, Bill Paspaliaris, Alan Riglar, Robyn McLachlan, and Brendan Murphy. "Primary sjögren’s syndrome and gamma heavy chain disease." Pathology 26, no. 3 (1994): 337–38. http://dx.doi.org/10.1080/00313029400169791.

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Dissertations / Theses on the topic "Gamma -heavy chain disease"

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GUGLIELMI, PAUL. "Etude moleculaire de deux cas de maladie des chaines lourdes." Paris 7, 1988. http://www.theses.fr/1988PA077069.

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Vera, Carlos D. "Functional Characterization of Disease-Causing Mutations in Human Myosin Heavy Chain Genes." Thesis, University of Colorado at Boulder, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10981347.

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Biophysical and biochemical imbalance of mechanisms relevant to muscle function, can result in morphological changes to the tissue. While the purpose of activities involving exercise is to modify the shape and size of skeletal muscle, and the length of these muscles allows wide ranges of stiffness and stretch to be applied, cardiac tissue is not meant to change much. However, stressful extrinsic factors (poor diet, chemotherapy, etc) or intrinsic factors like inherited mutations in muscle functioning genes can result in a myopathy or a disease of the muscle. In fact, another biological process that requires much compliance of many molecules is embryogenesis. Although the timeline of an embryonic structure is limited, compared to an adult heart and muscle composition, continuous and coordinated movement is essential, but cumulative, prolonged disruptions can be harmful. At the core of muscle biology is the myosin molecule which is a motor protein that hydrolyzes ATP, binds to actin, and the spatial dynamics of its function (contraction-relaxation) alter the length of muscle. Myosin cyclically follows specific steps and undertakes well-defined structural conformations during these events, but mutations can alter the time and stability of any of these aspects. In this thesis I did a comprehensive analysis of the ATPase cycle parameters for both embryonic and cardiac myosin and studied the effects of specific associated or linked mutations have on function. The multiple mutations were in the interest of cataloging common features and defects to identify mechanistic patterns. In a collaborative effort I also used these wet-lab measurements to simulate the cycle using a working kinetic model for the myosin ATPase cycle. We have found distinct differences between three different myopathies that will be discussed in the following chapters.

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Fernando, Tharu M. "TCDD-induced modulation of the hs1,2 enhancer within the 3’immunoglobulin heavy chain regulatory region." Wright State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=wright1247500080.

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Barri, Muruj Asaad. "Functional analysis of motor neuron disease-associated mutations in TAR DNA-binding protein 43 and cytoplasmic dynein heavy chain 1." Thesis, University of Sussex, 2015. http://sro.sussex.ac.uk/id/eprint/55342/.

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Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy with lower extremity predominance (SMA-LED) are two forms of motor neuron diseases at the opposite ends of the age spectrum, with ALS being mainly an adult-onset progressive and fatal neurodegenerative disease, and SMA-LED being a childhood-onset neuromuscular disease, manifested by muscle weakness, joint contracture, abnormal gait, and in some cases combined with intellectual disability. This thesis represents my research on the role of mutant forms of two proteins, namely Tar-DNA binding protein 43 (TDP-43) and cytoplasmic dynein heavy chain 1 (DYNC1H1) in the pathogenesis of ALS and SMA-LED, respectively. TDP-43 – an RNA/DNA binding protein – has been implicated in ALS. The function of TDP-43 in the nucleus is to regulate RNA processing, including RNA splicing and editing. Abnormal expression of the peripherin splice variant per61 has been found in transgenic mouse models of ALS. In addition, aberrant expression of EAAT2 (excitatory amino acid glutamate transporter 2) protein has been reported in some ALS cases. Thus, I investigated splicing of peripherin and GLT-1 (the murine homologue of EAAT2) RNAs, as potential targets of TDP-43 and examined whether mutations in TDP-43 alter the expression levels of the genes encoding the two proteins. My data show that per61 is expressed in wild type mice at both RNA and protein levels. This suggests a role for this isoform in the assembly of peripherin filaments. Moreover, overexpression of TDP-43A315T increases the expression level of per45 (an alternative translated isoform of peripherin) and leads to the instability of the filament network. Analysis of GLT-1B, the neuronal splice variant of GLT-1, reveals significant down-regulation in TDP-43A315T transgenic mice, indicating impaired RNA processing of GLT-1B. Collectively, these data show that the expression of peripherin and EAAT2 is regulated by TDP-43, and that aberrant expressions of these two genes caused by TDP-43 mutations could have a role in the pathology of ALS. A Phe580Tyr mutation in the mouse gene Dync1h1 impairs growth factor-induced endocytic trafficking in Dync1h1+/F580Y mouse motor neurons, resulting in aberrant activation of extracellular-signal-related kinases 1 and 2 (ERK1/2) and phosphorylation of the immediate early gene c-Fos. My data show that the induction of c-Fos upon serum starvation and/or growth factor stimulation is ERK1/2 dependent and that the mitogen-activated protein kinase p38 is also likely to be involved in c-Fos activation during starvation. Moreover, the activation of autophagy is reduced in Dync1h1+/F580Y motor neurons, suggesting a role for cytoplasmic dynein in autophagy induction/formation. In addition, the Dync1h1F580Y/F580Y mouse embryonic fibroblasts (MEFs) exhibit a defect in cell migration, as manifested by a delayed wound closure and reduced levels of paxillin phosphorylation at Tyr118 (p-paxillin). They also show abnormal and increased number of focal adhesions in spreading assays. Interestingly, human SMA-LED DYNC1H1R399G/R399G fibroblasts show defective lamellipodia formation, as well as reduced levels of p-paxillin. Moreover, Dync1h1+/F580Y mouse motor neurons show a defect in exploratory microtubules in the peripheral domain of their growth cones. As the molecular mechanism of growth cone motility is analogous to that found in fibroblasts, the molecular pathogenesis of SMA-LED caused by mutations in cytoplasmic dynein heavy chain 1, is likely to involve impaired growth cone development and axonal pathfinding, which could be exacerbated by the aberrant endocytic trafficking and signalling in mutant motor neurons.

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Li, Mingxin. "Celluar and Molecular Mechanisms Underlying Regulation of Skeletal Muscle Contraction in Health and Disease." Doctoral thesis, Uppsala universitet, Klinisk neurofysiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-123005.

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Morphological changes, genetic modifications, and cell functional alterations are not always parallel. Therefore, assessment of skeletal muscle function is an integral part of the etiological approach. The general objective of this thesis was to look into the cellular and molecular events occurring in skeletal muscle contraction in healthy and diseased condition, using a single fiber preparation and a single fiber in vitro motility assay, in an attempt to approach the underlying mechanisms from different physiological angles. In a body size related muscle contractility study, scaling of actin filament sliding speed and its temperature sensitivity has been investigated in mammals covering a 5,500-fold difference in body mass. A profound temperature dependence of actin filament sliding speed over myosin head was demonstrated irrespective of MyHC isoform expression and species. However, the expected body size related scaling within orthologus myosin isoforms between species failed to be maintained at any temperature over 5,500-fold range in body mass, with the larger species frequently having faster in vitro motility speeds than the smaller species. This suggest that apart from the MyHC iso-form expression, other factors such as thin filament proteins and myofilament lattice spacing, may contribute to the scaling related regulation of skeletal muscle contractility. A study of a novel R133W β-tropomyosin mutation on regulation of skeletal muscle contraction in the skinned single fiber prepration and single fiber in vitro motility assay suggested that the mutation induced alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin binding state, resulting in overall muscle weakness in the absence of muscle wasting. A study on a type IIa MyHC isoform missense mutation at the motor protein level demonstrated a significant negative effect on the function of the IIa MyHC isoform while other myosin isoforms had normal function. This provides evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle irrespective of MyHC isoform expression.

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Dambrun, Dit Tambrun Magalie. "Lymphocytes B et immunoglobulines néonatales dans un contexte d'infection parasitaire congénitale : stratégies méthodologiques de caractérisation Human immunoglobulin heavy gamma chain polymorphisms: molecular confirmation of proteomic assessment." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB118.

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Durant ses premiers mois de vie, le nouveau-né a la particularité d'être protégé par les immunoglobulines (Ig)G de sa mère, qui sont transférées au cours de la grossesse, et sont présentes dans son sérum conjointement aux IgG qu'il néo-synthétise. La distinction dans un sérum de nouveau-né, entre les IgG d'origine maternelle et fœtale, est difficile à mettre en œuvre, mais peut s'avérer très utile pour contribuer à diagnostiquer de façon précoce certaines infections congénitales, notamment dans le cas d'infections parasitaires. À ces fins, notre groupe de travail a mis en place une méthodologie reposant sur la spectrométrie de masse et qui exploite des polymorphismes peptidiques individuels localisés sur les domaines constants CH2 et CH3-CHS de la chaîne lourde des IgG. Nous proposons dans ce travail de valider cette approche par biologie moléculaire. L'amplification et le séquençage spécifiques des domaines constants CH2 et CH3-CHS des 4 sous-classes d'IgG totales ont permis i/de valider l'approche par spectrométrie de masse bottom-up et ii/de mettre en évidence de nouveaux polymorphismes nucléotidiques entraînant ou non un changement en acide aminé. Cette approche exige une purification exclusive des IgG spécifiques de pathogène, qui peut être contournée en utilisant une autre approche, cellulaire, reposant sur les IgG spécifiques sécrétées par les lymphocytes (Ly) B du nouveau-né. Ainsi, les spécificités individuelle et antigénique de l'Ig sont conciliées. Pour ce faire, un autre développement de mon travail a consisté dans l'adaptation de la technique ELISPOT (Enzyme-Linked ImmunoSpot), dans le cadre de la toxoplasmose, causée par le parasite Toxoplasma gondii, et responsable avec la maladie de Chagas de la plupart des cas d'infections congénitales d'origine parasitaire. Les mises au point ont été faites avec des cellules mononucléées d'adultes volontaires séronégatifs et séropositifs pour la toxoplasmose, qui nous ont conduits à faire le choix d'un lysat parasitaire de T. gondii de type I comme candidat antigénique multi-épitopes par rapport à la protéine recombinante spécifique SAG1 (Surface Antigen 1), protéine membranaire représentative du parasite. L'exploration d'autres paramètres est nécessaire pour compléter l'adaptation de l'ELISPOT dans le cadre précis d'une infection parasitaire congénitale. Il s'agit notamment d'évaluer i/la pertinence du test lors d'une infection récente avec T. gondii, en utilisant des LyB d'adultes en séroconversion et/ou de nouveau-nés ayant contracté une toxoplasmose congénitale, et ii/ l'ubiquité du test, en étudiant sa capacité à révéler avec une même efficacité les IgG sécrétées par des LyB d'individus infectés par des souches de toxoplasme circulant dans des zones géographiques différentes. Pour rendre possible cette dernière phase d'adaptation de l'ELISPOT, la mise en place d'études de terrain s'est imposée afin de constituer une bio-banque dans le cadre de suivis de la toxoplasmose chez des femmes enceintes et leurs nouveau-nés à l'accouchement : une première étude a été réalisée pendant 3 mois en 2018 dans la maternité d'un CHU à Cotonou au Bénin ; parallèlement un essai clinique est en cours pour 18 mois depuis juin 2018 dans 3 maternités d'hôpitaux de l'AP-HP en Ile de France. En supplément, une étude séro-épidémiologique rétrospective de la toxoplasmose chez environ 1000 femmes enceintes au sud du Bénin, à partir de plasmas collectés dans un projet mené en 2008-2010 dans notre UMR, permettra de documenter pour la première fois sur un aussi large effectif, la séroprévalence de la toxoplasmose chez des femmes enceintes au Bénin (53%) ainsi que le taux de séroconversion toxoplasmique pendant la grossesse (en cours). En plus des objectifs énoncés, l'ensemble de ces travaux contribue à mieux documenter l'exploration du système immunitaire fœtal
In the first months of life, the newborn is protected from infections by the maternal immunoglobulins (Ig) G, which are transferred during pregnancy, and are present in his serum together with his neo-synthesized IgG.The distinction in neonatal serum between maternal and fetal IgG is difficult to implement, but could be very useful for diagnosing congenital infections early, particularly in the case of parasitic infections. For this purpose, our team has established a methodology based on mass spectrometry that exploits individual peptide polymorphisms located on the CH2 and CH3-CHS domains from the constant IgG heavy chain. In this work, we propose to validate this approach by molecular biology. The specific amplification and sequencing of the CH2 and CH3-CHS constant domains of the 4 total IgG subclasses allowed i/to validate the bottom-up mass spectrometry approach and ii/to highlight new nucleotide polymorphisms causing or not an amino acid change. This approach requires an exclusive purification of pathogen-specific IgG, which can be circumvented using another cell-based approach, based on the specific IgG secreted by the newborn B lymphocytes (Ly). Thus, the individual and antigenic specificities of Ig are reconciled. To do this, another development of my work consisted in the adaptation of the ELISPOT technique (Enzyme-Linked ImmunoSpot), in the context of the toxoplasmosis, caused by Toxoplasma gondii parasite, and responsible with the Chagas disease of the most cases of congenital infections of parasitic origin. Developments were made with mononuclear cells from adult volunteers seronegative and seropositive for toxoplasmosis, which led us to select a parasitic T. gondii type I lysate as multi-epitopes antigenic candidate compared to the specific recombinant protein SAG1 (Surface Antigen 1), a membrane protein representative of the parasite. The investigation of other parameters is necessary to complete the ELISPOT adaptation in the specific context of congenital parasitic infection. These include assessing i/the suitability of the test in the case of a recent infection with T. gondii, using B Ly from seroconverting adults and/or neonates with congenital toxoplasmosis, and ii/the test ubiquity, by studying its ability to reveal with the same efficiency the IgG secreted by B Ly from individuals infected with toxoplasm strains circulating in different geographical areas. To make this last ELISPOT adaptation phase possible, the implementation of field studies was essential in order to constitute a bio-bank resulting from toxoplasmosis follow-ups of pregnant women and their newborns at childbirth: a first study was conducted for 3 months in 2018 in the CHU maternity in Cotonou, Benin; also, a clinical trial has been in progress for 18 months since June 2018 in 3 AP-HP hospitals maternities, in Ile de France. In addition, a retrospective sero-epidemiological study of toxoplasmosis in about 1000 pregnant women in southern Benin, was conducted, using plasma samples collected 2008-2010 in our unit. This will document for the first time toxoplasmosis seroprevalence on a wide effective of pregnant women in Benin (53%) as well as the rate of toxoplasmic seroconversion during pregnancy (ongoing). In addition to the stated objectives, all of this work contributes to better documenting the exploration of the fetal immune system

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Massara, Layal. "Cytomégalovirus : réponse des lymphocytes T γδ et impact sur le développement tumoral." Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0165.

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Le cytomégalovirus (CMV), un β-herpes virus, est considéré comme un modèle d'immuno-évasion virale. Il s'agit d'un agent pathogène opportuniste fréquent chez les patients immunodéprimés et une cause majeure de malformations congénitales lors de l'acquisition in utero. Le CMV code pour des protéines (i) qui empêchent la présentation de l'antigène aux lymphocytes T αβ notamment par l'inhibition de l'expression des molécules HLA-I et (ii) qui suppriment les fonctions des cellules NK en imitant ou en régulant à la baisse les ligands des récepteurs NK (NKR). Ces mécanismes d'évasion ne devraient pas affecter les lymphocytes T γδ dont la reconnaissance antigénique est indépendante du HLA-I, et d’ailleurs leur réponse au CMV a été largement rapportée dans de nombreux contextes physiopathologiques. Notre objectif était de comprendre comment les mécanismes d’immuno-évasion du CMV affectent la réponse des lymphocytes T γδ. Nous avons utilisé des adénovirus recombinants exprimant chacun des quatre gènes du CMV impliqués dans l’inhibition de l’expression du HLA-I, et un mutant du HCMV déficient pour ces 4 gènes (CMV-∆US). Nous avons observé une induction de l'expression de HLA-I par l'adénovirus control, et une inhibition par US2, US3 et US11. Lors de l'utilisation de CMV-∆US, les cellules infectées exprimaient beaucoup plus de HLA-I que les cellules infectées par CMV-WT. De façon intéressante et à l’opposé des lymphocytes T αβ, les lymphocytes T γδ produisent plus d'IFNy en présence de fibroblastes infectés par le CMV-WT, qu’avec des fibroblastes infectés par CMV-∆US. Ces résultats indiquent que les molécules HLA-I régulent les lymphocytes T γδ grâce à des mécanismes qui sont en cours d'investigation dans notre équipe. Les processus d'échappement immunitaire développés par le CMV pourraient ainsi favoriser la réponse des lymphocytes T γδ par rapport à celle des lymphocytes T αβ et expliquer le rôle important des cellules T γδ dans le contrôle du virus chez les individus immunodéprimés. D'autre part, les acides nucléiques et les protéines du HCMV ont été trouvés dans les tissus tumoraux, mais la relation précise entre le HCMV et le cancer reste un sujet de débat. La plupart du temps, HCMV est décrit comme un virus oncomodulateur avec un rôle pro-tumoral. Notre objectif était d'utiliser le modèle de la souris pour tester in vivo l'impact de CMV de souris (MCMV) sur la croissance des cellules tumorales. Nous avons observé que MCMV pourrait inhiber la croissance de tumeurs sous-cutanées de côlon MC38 chez les souris immunodéficientes. Encore plus surprenant lorsque l'on considère la spécificité d’espèce des CMV, l'infection par le MCMV inhibe de la même façon la croissance des cellules cancéreuses du côlon humain HT29, qui n’est pas affectée par le HCMV. In vitro, les protéines MCMV précoces (IE-1) sont détectées dans des cellules cancéreuses humaines et murines après l'infection. Cependant, peu de cellules cancéreuses sont retrouvées positives pour le MCMV dans les tumeurs HT29 prélevées sur des souris infectées par le MCMV. De manière surprenante, le MCMV inhibe la prolifération des cellules cancéreuses de côlon humain contrairement au HCMV. De plus, la transcription de l'interféron β humain est induite après une infection par le MCMV. Cette induction n'a pas été observée après l'infection par le HCMV. En conclusion, nos données suggèrent un potentiel effet anti-tumoral de MCMV sur les cellules cancéreuses du côlon humain (HT29), qui pourrait être au moins partiellement médiée par l'interféron β. Ces résultats ouvrent la voie à l'utilisation potentielle du MCMV en tant que traitement du cancer du côlon humain
Cytomegalovirus (CMV), a Beta Herpes virus, is considered as a paradigm for viral evasion.It is an important opportunistic pathogen in immunocompromised patients and a major cause of congenital birth defects when acquired in utero. CMV encodes molecules to prevent antigen presentation to αβ T cells through inhibition of MHC Class I expression and to suppress NK cell functions by mimicking or down-regulating ligands of NK receptors (NKR). These evasion mechanisms are not expected to affect γδ T cells and, as a matter of fact, their response to CMV has been widely reported in many different physiopathological contexts as well as in CMV-seropositive healthy donors (Dechanet et al, 1999)( Scheper, 2013). Our aim was to understand how CMV induce γδ T cell response. We used recombinant adenoviruses expressing each of the four US genes, and a mutant HCMV deleted for these 4 genes (CMV-DUS). We observed an induction of HLA-I expression by the control adenovirus, and an inhibition by US2, US3 and US11. When using CMV-DUS, infected cells expressed much more native HLA-I than CMV-WT infected cells. Interestingly and in sharp contrast to αβ T cells, γδ T cell were activated to produce IFNg when cultured with fibroblasts infected with CMV-WT, but not when fibroblasts were infected with CMV-DUS. These results indicate that HLA-I molecules regulate γδ T cells through mechanisms that are under investigation in our team. The immune escape processes developed by CMV could thus promote γδ over αβ T cell response and explain the important response of γδ T cells to the virus in immunosuppressed individuals

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Chehtane, Mounir. "REAL TIME REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION FOR DIRECT DETECTION OF VIABLE MYCOBACTERIUM AVIUM SUBSPECIES PARATUBERCULOSIS IN CROHN S DISEASE PATIENTS and ASSOCIATION OF MAP INFECTION WITH DOWNREGUALTION IN INTERFERON-GAMMA RECEPTOR (INFG." Master's thesis, University of Central Florida, 2005. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4281.

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Association of Mycobacterium avium subspecies paratuberculosis (MAP) with Crohn's disease (CD) and not with ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), has been vigorously debated in recent years. This theory has been strengthened by recent culture of MAP from breast milk, intestinal tissue and Blood from patients with active Crohn's disease. Culture of MAP from clinical samples remained challenging due to the fastidious nature of MAP including its lack of cell wall in infected patients. The advent of real time PCR has proven to be significant in infectious disease diagnostics. In this study, real time reverse transcriptase PCR (RT-PCR) assay based on targeting mRNA of the IS900 gene unique to MAP has been developed. All variables included in RNA isolation, cDNA synthesis and real time PCR amplification have been optimized. Oligonucleotide primers were designed to amplify 165 bp specific to MAP and the assay demonstrated sensitivity of 4 genomes per sample. In hope this real time RT-PCR may aid in the detection of viable MAP cells in Crohn's disease patients, a total of 45 clinical samples were analyzed. Portion of each sample was also subjected to 12 weeks culture followed by standard nested PCR analysis. The samples consisted of 17 cultures (originated from 13 CD, 1 UC and 3 NIBD subjects), 24 buffy coat blood (originated from 7 CD, 2 UC, 11 NIBD and 4 healthy subjects) and 4 intestinal biopsies from 2 CD patients. Real time RT-PCR detected viable MAP in 11/17 (65%) of iii suspected cultures compared to 12/17 (70%) by nested PCR including 77% and 84% from CD samples by both methods, respectively. Real time RT-PCR detected MAP RNA directly from 3/7 (42%) CD, 2/2 (100%) UC and 0/4 healthy controls similar to results following long term culture incubation and nested PCR analysis. Interestingly, real time RT-PCR detected viable MAP in 2/11 (13%) compared to 4/11 (26%) by culture and nested PCR in NIBD patients. For tissue samples, real time RT-PCR detected viable MAP in one CD patient with the culture outcome remains pending. This study clearly indicates that a 12-hr real time RT-PCR assay provided data that are similar to those from 12 weeks culture and nested PCR analysis. Consequently, use of real time In our laboratory, we previously demonstrated a possible downregulation in the Interferon-gamma receptor gene (IFNGR1) in patients with active Crohn's disease using microarray chip analysis. In this study, measurement of RNA by real time qRT-PCR indicated a possible downregulation in 5/6 CD patients compared to 0/12 controls. The preliminary data suggest that downregulation in INFGR1 gene, and the detection of viable MAP in CD patients provides yet the strongest evidence toward the linkage between MAP and CD etiology.
M.S.
Department of Molecular Biology and Microbiology
Burnett College of Biomedical Sciences
Molecular Biology and Microbiology

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Nakamura, Naohiko. "Elevated levels of circulating ITIH4 are associated with hepatocellular carcinoma with nonalcoholic fatty liver disease: From pig model to human study." Doctoral thesis, Kyoto University, 2020. http://hdl.handle.net/2433/245833.

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京都大学
0048
新制・課程博士
博士(医学)
甲第22148号
医博第4539号
新制||医||1039(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授坂井義治, 教授小西靖彦, 教授滝田順子
学位規則第4条第1項該当
Doctor of Medical Science
Kyoto University
DFAM

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Bonaud, Amélie. "Maturation finale des lymphocytes B : de la commutation de classe aux conséquences pathologiques de la production d'immunoglobulines anormales." Thesis, Limoges, 2015. http://www.theses.fr/2015LIMO0017/document.

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La commutation de classe (CSR) est une étape clef de la réponse immunitaire. Ce phénomène va permettre de changer le type d’immunoglobuline (Ig) produite en réponse à un antigène donné. Ces Ig seront ensuite produites par les plasmocytes, qui constituent le stade ultime de la différenciation de la lignée cellulaire B. Lors de dérèglements de la prolifération de ces cellules, certaines Ig monoclonales anormales peuvent être produites et conduire à des situations pathologiques. La première partie de ce travail s’inscrit dans une logique de compréhension des éléments minima requis pour l’établissement de ce phénomène de CSR. Grace à un modèle animal d’insertion dirigée dans le locus kappa murin, naturellement ciblé par l’enzyme AID responsable de ce phénomène, nous avons mis en évidence que la présence de deux régions « switch » transcrites et fortement mutées par AID, n’était pas suffisante pour permettre ce phénomène. Un modèle murin reproduisant une maladie due à une Ig anormale a aussi été établi. Ce modèle de HCDD (Heavy Chain Deposition Disease) nous a permis de mettre en évidence la nécessité de la délétion du CH1 des chaînes lourdes d’Ig pour la génération des dépôts et nous a également permis de montrer que l’efficacité des thérapies à base d’inhibiteur de protéasome observée chez les patients atteint de HCDD, était en partie due à l’Ig pathogène elle-même, qui induit une élévation du stress du réticulum endoplasmique (UPR) au sein des plasmocytes producteurs de ces Ig
Class Switch Recombination (CSR) is a key step during the immune response. CSR results in a switch to a more specific Ig isotype in response to a specific antigen. Plasma cells, the ultimate stage of B cell lineage differentiation, will synthesize this Ig. During plasma cell disorders, the production of an abnormal monoclonal Ig can lead to pathogenic situations. The aim of the first part of this study is to determine the minimal requirements for CSR induction with a mouse model in which we inserted a “switch cassette” composed of two transcribed S regions into a kappa locus which is naturally targeted by AID. However, despite efficient transcription and AID targeting of S regions, the “switch cassette” was not sufficient to induce effective CSR. We also developed a mouse model of HCDD (Heavy Chain Deposition Disease) which reproduced typical Randall-type renal lesions due to production of a pathogenic truncated heavy chain. This model demonstrated that the effective response to proteasome inhibitors observed in patients, is the consequence of the presence of a truncated HC that sensitizes plasma cells to this type of therapy through an elevated unfolded protein response (UPR)

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Books on the topic "Gamma -heavy chain disease"

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McCully, James Donald *. Myocardial cell gene regulation during the aging and cardiomyopathic disease processes: characterization of a Syrian hamster myosin heavy chain gene. 1989.

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Turner, Neil, and Bertrand Knebelmann. MYH9 and renal disease. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0342_update_001.

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MYH9 encodes one of three heavy chain isoforms for the non-muscle myosin II (NM II) molecule. NM II is involved in cell structure and shape and motility. Myosin II is very widely expressed but MYH9 is highly expressed in podocytes. MYH9 diseases are characterized by various combinations of autosomal dominant progressive, proteinuric renal disease, giant platelets with low platelet counts, progressive sensorineural hearing impairment, granulocyte inclusions, and in some patients also cataracts. Although the eponyms Epstein and Fechtner have been given to MYH9 renal syndromes, there is a spectrum of manifestations of MYH9 diseases that do not correlate perfectly with genotype. They are best described as MYH9-associated renal disease. The occurrence of progressive deafness and renal failure led to this condition being considered an Alport syndrome variant in the past, but phenotype as well as molecular genetics clearly separate the disorders.

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Fervenza, Fernando C., An S. De Vincent Rajkumar, An S. De Vriese, and Sanjeev Sethi. Other consequences from monoclonal immunoglobulins/fragments. Edited by Giuseppe Remuzzi. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0155_update_001.

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Renal damage secondary to deposition of monoclonal immunoglobulin can occur due to accumulation of either light chains, heavy chains, or both. These include myeloma kidney (cast nephropathy), light-chain and heavy-chain amyloidosis, and light- and heavy-chain deposition disease. Renal damage secondary to deposition of both chains is far less common. In the great majority of these cases the M-component is immunoglobulin G, but the spectrum of renal lesions associated with monoclonal gammopathy is extensive and depends on the physiochemical properties of the immunoglobulin produced.This chapter discusses two important, but less recognized disorders associated with monoclonal immunoglobulins: membranoproliferative glomerulonephritis and acquired Fanconi syndrome.

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Provan, Drew, Trevor Baglin, Inderjeet Dokal, and Johannes de Vos. Paraproteinaemias. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199683307.003.0008.

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Paraproteinaemias - Monoclonal gammopathy of undetermined significance (MGUS) - Asymptomatic multiple myeloma (‘smouldering’ myeloma) - Multiple myeloma - Variant forms of myeloma - Cryoglobulinaemia - POEMS syndrome (osteosclerotic myeloma) - Plasmacytoma - Waldenström macroglobulinaemia - Heavy chain disease - AL (1° systemic) amyloidosis

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Provan, Drew, Trevor Baglin, Inderjeet Dokal, Johannes de Vos, and Mammit Kaur. Paraproteinaemias. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199683307.003.0008_update_001.

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Paraproteinaemias - Monoclonal gammopathy of undetermined significance (MGUS) - Asymptomatic multiple myeloma (‘smouldering’ myeloma) - Multiple myeloma - Variant forms of myeloma - Cryoglobulinaemia - POEMS syndrome (osteosclerotic myeloma) - Plasmacytoma - Waldenström macroglobulinaemia - Heavy chain disease - AL (1° systemic) amyloidosis

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Steensma, David P. Malignant Hematology. Oxford University Press, 2012. http://dx.doi.org/10.1093/med/9780199755691.003.0296.

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The hematologic neoplasms include lymphoproliferative disorders (eg, chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], large granular lymphocyte leukemia, hairy cell leukemia [HCL], Hodgkin lymphoma, non-Hodgkin lymphoma), plasma cell disorders (multiple myeloma, light chain amyloidosis, Waldenström macroglobulinemia, POEMS syndrome, heavy chain disease, plasmacytoma), chronic myeloid neoplasms (chronic myeloid leukemia, the BCR/ABL-negative myeloproliferative neoplasms, myelodysplastic syndromes), and acute leukemia (acute myeloid leukemia, acute lymphocytic leukemia). In addition, clonal but not overtly malignant conditions are common in the general population, including monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B lymphocytosis (MBL).

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Lai, Kar Neng, and Sydney C. W. Tang. Immunoglobulin A nephropathy. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0069_update_001.

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A working hypothesis is that patients with immunoglobulin A (IgA) nephropathy have inherited defects in B cells producing galactose-deficient polymeric IgA1. Additional cofactors are required to form immune complexes and their deposition in glomeruli. Molecular characterization of IgG autoantibodies that recognize abnormally underglycosylated IgA1 reveals a specific amino acid substitution in the variable region of the IgG1 heavy chain. This substitution greatly enhances IgG1 binding to the galactose-deficient IgA1. The triggering antigens may include viral or bacterial antigens, or possibly by ingested food epitopes. Antiglycan IgG1 antibodies are one of the additional risk factors, or a second/multiple hit, which predisposes to disease development.

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Ronco, Pierre M. Kidney involvement in plasma cell dyscrasias. Edited by Giuseppe Remuzzi. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0150.

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Monoclonal proliferations of the B-cell lineage are characterized by abnormal and uncontrolled expansion of a single clone of B cells at different maturation stages, with a variable degree of differentiation to immunoglobulin-secreting plasma cells. Therefore, they are usually associated with the production and secretion in blood of a monoclonal immunoglobulin and/or a fragment thereof which may become deposited in tissues. These deposits can take the form of casts (in myeloma cast nephropathy), crystals (in myeloma-associated Fanconi syndrome), fibrils (in light-chain and exceptional heavy-chain amyloidosis), or granular precipitates (in monoclonal immunoglobulin deposition disease). They may disrupt organ structure and function, inducing life-threatening complications. All of the pathologic entities related to immunoglobulin deposition principally involve the kidney, which is not only explained by the high levels of renal plasma flow and glomerular filtration rate, but also by the sieving properties of the glomerular capillary wall and by the prominent role of the renal tubule in LC handling and catabolism.The different renal (and other) manifestations are related to the unique physicochemical characteristics of each paraprotein or immunoglobulin fragment, and the rate of their production.

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Book chapters on the topic "Gamma -heavy chain disease"

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Wahner-Roedler, Dietlind L., and Robert A. Kyle. "Heavy-Chain Disease." In Neoplastic Diseases of the Blood, 701–28. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4614-3764-2_36.

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Jákó, János. "The heavy chain disease." In Gammopathy, 161–76. Berlin, Heidelberg: Springer Berlin Heidelberg, 1991. http://dx.doi.org/10.1007/978-3-642-84929-9_7.

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Oette, Mark, Marvin J. Stone, Hendrik P. N. Scholl, Peter Charbel Issa, Monika Fleckenstein, Steffen Schmitz-Valckenberg, Frank G. Holz, et al. "Myosin Heavy Chain IIa Myopathy, Autosomal Dominant." In Encyclopedia of Molecular Mechanisms of Disease, 1421–22. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_1230.

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Scharnagl, Hubert, Winfried März, Markus Böhm, Thomas A. Luger, Federico Fracassi, Alessia Diana, Thomas Frieling, et al. "Autosomal Dominant Myosin Heavy Chain IIa Myopathy." In Encyclopedia of Molecular Mechanisms of Disease, 196. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_9061.

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Herrera, Guillermo A., and Elba A. Turbat-Herrera. "Light/Heavy Chain Deposition Disease as a Systemic Disorder." In Amyloid and Related Disorders, 129–41. Totowa, NJ: Humana Press, 2012. http://dx.doi.org/10.1007/978-1-60761-389-3_9.

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Herrera, Guillermo A., and Elba A. Turbat-Herrera. "Light/Heavy Chain Deposition Disease as a Systemic Disorder." In Current Clinical Pathology, 153–66. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-19294-9_10.

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Yamashita, Hiroshi, Seiryo Sugiura, Hideo Fujita, Soichiro Yasuda, Ryozo Nagai, Yasutake Saeki, and Haruo Sugi. "Myosin Heavy Chain Isoforms Modulate Motor Function of Cardiac Myosin by Changing Crossbridge Kinetics." In Pathophysiology of Cardiovascular Disease, 35–49. Boston, MA: Springer US, 2004. http://dx.doi.org/10.1007/978-1-4615-0453-5_3.

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Zhou, Qi, Li Yu, and Fang-Ding Lou. "Detection of Minimal Residual Disease by Immunoglobulin Heavy Chain Gene Rearrangement Analysis in Patients with Ball after Bone Marrow Transplantation." In Bone Marrow Transplantation, 274–76. Tokyo: Springer Japan, 1996. http://dx.doi.org/10.1007/978-4-431-68320-9_36.

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Kamisago, Mitsuhiro, Joachim P. Schmitt, Dennis McNamara, Christine Seidman, and J. G. Seidman. "Sarcomere Protein Gene Mutations and Inherited Heart Disease: A β Cardiac Myosin Heavy Chain Mutation Causing Endocardial Fibroelastosis and Heart Failure." In Novartis Foundation Symposia, 176–95. Chichester, UK: John Wiley & Sons, Ltd, 2008. http://dx.doi.org/10.1002/0470029331.ch11.

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Pino, Steve, Michael A. Brehm, Laurence Covassin-Barberis, Marie King, Bruce Gott, Thomas H. Chase, Jennifer Wagner, et al. "Development of Novel Major Histocompatibility Complex Class I and Class II-Deficient NOD-SCID IL2R Gamma Chain Knockout Mice for Modeling Human Xenogeneic Graft-Versus-Host Disease." In Methods in Molecular Biology, 105–17. Totowa, NJ: Humana Press, 2006. http://dx.doi.org/10.1007/978-1-60761-058-8_7.

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Conference papers on the topic "Gamma -heavy chain disease"

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Quertermous, T., J. M. Schnee, M. S. Runge, G. R. Matsueda, N. W. Hudson, J. G. Seidman, and E. Haber. "EXPRESSION OF A RECOMBINANT ANTIBODY-TARGETED THROMBOLYTIC MOLECULE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644616.

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We have recently shown that targeting tissue-type plasminogen activator (t-PA) by covalent linkage to a fibrin-specific monoclonal antibody (59D8) produces a more potent thrombolytic agent which also induces less fibrinogenolysis. A recombinant molecule encoding a t-PA-59D8 fusion protein was constructed to provide a ready source of this agent for further study, and to allow tailoring of the active moities for maximal activity. DNA sequence coding for the 59D8 heavy chain (HC) antigen combining site was cloned from a lambdaphage library by selection with a joining region probe. Gene segments coding for this cloned HC rearrangement, the amino portion of the mouse gamma 2b HC constant region, and the catalytic B chain of t-PA were joined in the pSV2-gpt expression vector. The desired coding sequence was confirmed by nucleotide sequence analysis. The construct was transfected by electroporation into 59D8 hybridoma HC loss variants. Transfectants were screened for antifibrin antibody activity. Positive clones were shown to produce mRNA which hybridized to the human t-PA gene in Northern blot analysis. Supernatants from 5 of these clones were subjected to affinity chromatography on a synthetic fibrin-like peptide-Sepharose column followed by a benzamidine-Sepharose column. Western blots of SDS polyacrylamide gels run under reducing conditions revealed binding to a 60 kd band by a monoclonal antihuman t-PA antibody, consistent with a 59D8 HC-t-PA fusion protein. Also, binding to a 25 kd band by goat anti-mouse Fab indicated the presence of 59D8 light chain. Affinity purified protein was shown to have amidolytic activity of similar potency to t-PA in a chromogenic substrate assay utilizing S-2288. Bifunctionality of the purified protein was demonstrated first by an assay which requires the protein to bind to immobilized fibrin and simultaneously exhibit activity in the S2288 assay, and second by simultaneous fibrin and iodinated anti-t-PA binding.

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Haber, Edgar, Marchall T. Runge, Christoph Bode, Betsy Branscomb, and Janet Schnee. "ANTIBODY TARGETED FIBRINOLYSIS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643723.

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Chemical conjugates of fibrin-specificantibodies and plasminogen activators. Urokinase or tPA were linked covalently toamonoclonal antibody specific for the amino terminus of the beta chain of human fibrin (59D8) by means of the unidirectionalcross-linking reagent SPDP. The fibrinolytic potency of the conjugates at equal amidolytic activities was compared to the native plasminogen activators in an assay measuring lysis of 1251-fibrin monomer covalently linked to Sepharose CL-4B. Urokinase was least potent, tPA exhibited a 10fold increase in fibrinolysis whereas both the urokinase and tPA antibody conjugates and a urokinase-Fab conjugate were 250fold more potent than urokinase and 25 fold more potent than tPA. Enhanced fibrinolysis was fully inhibited by b peptide indicating its dependence on antigen binding. In a plasma assay conjugates of tPA orUK to antibody produced a 3.2- to 4.5-fold enhancement in clot lysis in human plasma over that of the respective unconjugated plasminogen activator. However, the UK-59D8 conjugate was only as potent as tPAalone. Antibody-conjugated tPA or UK consumed less fibrinogen, alpha 2-antiplasminand plasminogen than did the unconjugatedactivators, at equipotent thrombolytic concentrations. In a quantitative rabbit thrombolysis model, the activity of the purified conjugate was compared with that oftPA alone and that of a conjugate betweentPA and a digoxin-specific monoclonal antibody. After correction for spontaneous lysis, tPA-59D8 was shown to be 2.8 to,9.6times more potent than tPA alone. Unconjugated tPA and tPA-digoxin were equipotent.At equivalent thrombolytic concentrations, tPA-59D8 degraded less fibrinogen and consumed less alpha 2-antiplasmin than did tPA alone. These results suggest that tPA can be efficiently directed to the site of a thrombus by conjugation to an antifibrin monoclonal antibody, resulting in both more potent and more selective thrombolysis.A recombinant fusion protein comprising a fibrin-specific antibody site and theB chain of tPA. The rearranged 59D8 heavychain gene was cloned and combined in theexpression vector pSV2gpt withsequence coding for a portion of the Gamma 2b constant region and the catalytic beta chain of t-PA. This construct was transfected into heavy chain loss variant cells derived from the 59D8 hybridoma. Recombinant protein was purified by affinitychromatography and analyzed with Western blots. These revealed a 65-kD heavy chain-t-PA fusion protein that is secreted in association with the 59D8 light chain in the form of a 170-kD disulfide linked dimer. A chromogenic substrate assay showed the fusion protein to have 70 percent of the peptidolytic activity of native t-PA and to activate plasminogen as efficiently as t-PA. In a competitive binding assay, reconstituted antibody was shown to have a binding profile similar to that of native 59D8. Thus by recombinant techniques we have produced a novel hybrid protein capable of high affinity fibrin binding andplasminogen activation.Chemical conjugates between a fibrin-specific and a tPA-specific antibody. A heteroantibody duplex (duplex) with specificities for both tPA and fibrin was synthesized by conjugating iminothiolane-modified anti-tPA monoclonal antibody (TCL8) toantifibrin antibody 59D8. Addition of both duplex and tPA to a plasma clot assay gave more lysis (200 units produced 23.1 lysis; 400 units, 29.5 lysis) than did tPAalone (200 units, 1.8% lysis; 400 units,19% lysis). Despite increased potency associated with duplex addition, fibrinogen and alpha-2-antiplasmin levels at equal tPA concentrations did not differ. Thus, itis possible to concentrate tPA (added separately) to the site of a thrombus in plasma using a heteroantibody duplex with specificities for both tPA and fibrin.Biosynthetically produced heteroduplexantibodies that are both fibin and tPA-specific. The bispecific antibodies were prepared in two ways. First, polyethylene glycol-mediated fusions were performed with two different hybridoma cell lines: anti-fribrin b chain producer, 59D8 and anti-tPA producer, TCL8. TCL8 cells were selected for HPRT-minus variants and then fused with TK-deficient 59D8 cells. One cell line, F36.23, possessed both anti-human fibrin and anti-human t-PA immunoreactivities. A second method yielded another bispecific antibody, F32.1. This cell line was selected after fusing TCL8 (HPRT-minus) cells with spleen cells from a mouseimmunized with a fibrin-like peptide corresponding to the amino terminus of fibrinalpha-chains. Affinity-purified F32.1 andF36.23 retained anti-fibrin and anti-t-PAactivity and enhanced fibrinolytic potency of tPA by a factor of 10.

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Joost, S., A. Koedam, Joost C. M. Meijers, Jan J. Sixma, and Bonno N. Bouma. "VON WILLEBRAND FACTOR PROTECTS FACTOR VIII FROM INACTIVATION BY ACTIVATED PROTEIN C AND PROTEIN S." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643618.

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Activated protein C (APC) inactivated the cofactors factor V (FV) and factor VIII (FVIII). In the case of FV, this reaction and the respective roles of Ca2+ , phospholipids and protein S have been well documented. We investigated the role of protein S and von Willebrand factor (VWF) on the inactivation of FVIII.Purified human factor VIII (3 units/ml) was incubated with protein C (0.2 μg/ml) in the presence of 8 μg/ml phospholipid, 5 mM CaCl, and 1 unit/ml hirudin. Factor VIII coagulant activity decreased with a pseudo first-order rate constant of 0.09 min . The reaction rate increased linearly with the concentration of prot^ig S in the incubation mixture. 12I-FVIII was incubated under the same conditions. SDS-polyacrylamide gel electrophoresis showed cleavage products of Mr 43 and 22 kDa. High Mr bands (FVIII-heavy chain) ranging fromMr 108 to208 kDa disappeared while the Mr 80 kDa FVIII-lightchain remained unchanged. The degradationpattern was not changed by addition of protein S.The FVIII-VWF complex was reconstitutedby mixing the two components (±2 units VWF/units FVIII) and lowering the calcium concentration to 2 mM. The inactivation of the FVIII-VWF complex by APC proceeded at a 15- to 20-fold slower rate as compared to the isolated FVIII, indicating a protection of FVIII by VWF. Protein S exhibited no cofactor activity on the inactivation of FVIII-VWF by APC. The protective effect of VWF was lost completely after activation of the FVIII-VWF complexwith thrombin (0.05 units/ml).When FVIII (0.1 units/ml) was added toplasma of a patient with severe von Willebrand's disease, 96% of its activitywas lost in 20 min after the addition of APC. All of the FVIII activity was retained when haemophilic plasma was used. Mixing experiments showed that one unit ofVWF unit FVIII is needed to fully protec FVIII against APC. These results may explain the observed lability of FVIII in von Willebrand's disease patients.

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