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"Lyons, Jonathan"
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Islam through Western eyes : from the crusades to the war on terrorism
\"In Islam Through Western Eyes, Jonathan Lyons unpacks Western habits of thinking and writing about Islam, conducting a careful analysis of the West's grand totalizing narrative across one thousand years of history. He observes the discourse's corrosive effects on the social sciences, including sociology, politics, philosophy, theology, international relations, security studies, and human rights scholarship. He follows its influence on research, speeches, political strategy, and government policy, preventing the West from responding effectively to its most significant twenty-first-century challenges: the rise of Islamic power, the emergence of religious violence, and the growing tension between established social values and multicultural rights among Muslim immigrant populations.\"--Jacket.
Book
Alpha-Tryptase as a Risk-Modifying Factor for Mast Cell–Mediated Reactions
Purpose of ReviewTo provide an overview on the current understanding of genetic variability in human tryptases and summarize the literature demonstrating the differential impact of mature tryptases on mast cell–mediated reactions and associated clinical phenotypes.Recent FindingsIt is becoming increasingly recognized that tryptase gene composition, and in particular the common genetic trait hereditary alpha-tryptasemia (HαT), impacts clinical allergy. HαT has consistently been associated with clonal mast cell disorders (MCD) and has also been associated with more frequent anaphylaxis among these patients, and patients in whom no allergic trigger can be found, specifically idiopathic anaphylaxis. Additionally, more severe anaphylaxis among Hymenoptera venom allergy patients has been linked to HαT in both retrospective and prospective studies. An increased relative number of α-tryptase-encoding gene copies, even in the absence of HαT, has also been associated with systemic mastocytosis and has been shown to positively correlate with the severity of mast cell–mediated reactions to vibration and food. These findings may be due to increased generation of α/β-tryptase heterotetramers and differences in their enzymatic activity relative to β-tryptase homotetramers.SummaryHαT is a naturally occurring overexpression model of α-tryptase in humans. Increased relative α-tryptase expression modifies immediate hypersensitivity symptoms and is associated with more frequent and severe mast cell–mediated reactions, ostensibly due to increased α/β-tryptase heterotetramer production.
Journal Article
بيت الحكمة : كيف أسس العرب لحضارة الغرب
يضيء الكاتب \"جوناثان ليونز\" من خلال كتابه \"بيت الحكمة\" على حضارة وإسهامات العرب في بناء الحضارة الإنسانية فيما سمي بالعصر الذهبي لحضارة العرب والكاتب عد بالزمن للوراء وسترى أن من المستحيل تصور الحضارة الغربية من دون ثمار العلم العربي فن الجبر للخوارزمي أو التعاليم الطبية والفلسفية الشاملة لابن سينا أو علم الجغرافيا وفن رسم الخرائط للإدريسي المستمرين إلى اليوم أو العقلانية الصارمة لابن رشد بل الأهم من عمل أي شخص فرد كانت المساهمة الإجمالية للعرب تلك التي تقع في صميم الغرب المعاصر أي إدراك أن العلم يمكن أن يمنح الإنسان القدرة على تسخير الطبيعة.
Book
Hereditary Alpha-Tryptasemia: a Commonly Inherited Modifier of Anaphylaxis
Purpose of ReviewHereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait and a common cause of elevated basal serum tryptase in Western populations. It is a risk factor for severe anaphylaxis among individuals with venom allergy and an established modifier of anaphylaxis and mast cell mediator–associated symptoms among patients with systemic mastocytosis. Understanding the physiology of tryptases and how this may relate to the clinical features associated with HαT is the first step in identifying optimal medical management and targets for novel therapeutics.Recent FindingsHαT prevalence is increased in both clonal and non-clonal mast cell–associated disorders where it augments symptoms of immediate hypersensitivity, including anaphylaxis. The unique properties of naturally occurring α/β-tryptase heterotetramers may explain certain elements of phenotypes associated with HαT, though additional mechanisms are being evaluated.SummaryThis review provides an overview of the clinical and translational studies that have identified HαT as a modifier of mast cell–associated disorders and anaphylaxis and discusses mechanisms that may potentially explain some of these clinical findings.
Journal Article
Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease
Ivona Aksentijevich and colleagues identify heterozygous loss-of-function mutations in
TNFAIP3
(encoding A20) in six unrelated families with early-onset systemic inflammation. Affected individuals exhibit increased expression of NF-κB–mediated proinflammatory cytokines, consistent with the established role of A20 as a potent inhibitor of the NF-κB signaling pathway.
Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity
1
. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in
TNFAIP3
, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood
2
. A20 is a potent inhibitor of the NF-κB signaling pathway
3
. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB–mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB–dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.
Journal Article
Germline hypomorphic CARD11 mutations in severe atopic disease
Erwin Gelfand, Andrew Snow, Joshua Milner and colleagues identify heterozygous
CARD11
mutations associated with severe atopic disease in eight individuals from four families. They further show that the mutant CARD11 proteins exhibit both loss-of-function and dominant-interfering activity and that the cellular defects in patient T cells can be partially rescued by supplementing with glutamine.
Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in
CARD11
, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor–induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in
CARD11
can cause potentially correctable cellular defects that lead to atopic dermatitis.
Journal Article
Clinically accessible amplitude-based multiplex ddPCR assay for tryptase genotyping
Hereditary α tryptasemia (HαT) is an autosomal dominant trait characterized by increased
TPSAB1
copy number (CN) encoding α-tryptase. The determination of HαT is being discussed as an important biomarker to be included in risk assessment models and future diagnostic algorithms for patients with mastocytosis and anaphylaxis. Due to the complex genetic structure at the human tryptase locus, genetic testing for tryptase gene composition is presently notably limited and infrequently pursued. This study aimed to develop, optimise and validate a multiplex droplet digital PCR (ddPCR) assay that can reliably quantify α- and β-tryptase encoding sequences in a single reaction. To optimise the ddPCR conditions and establish an amplitude-based multiplex ddPCR assay, additional primers and probes, a thermal gradient with varying annealing temperatures, different primers/probe concentrations, and various initial DNA quantities were tested. Results obtained from all 114 samples analysed using multiplex ddPCR were identical to those obtained through the use of original duplex assays. Utilizing this multiplex ddPCR assay, in contrast to conducting distinct duplex ddPCRs, presents noteworthy benefits for tryptase genotyping. These advantages encompass a substantial threefold decrease in material costs and considerable time savings. Consequently, this approach exhibits high suitability and particularly captures interest for routine clinical implementation.
Journal Article
Mast cell activation in the context of elevated basal serum tryptase: genetics and presentations
Purpose of ReviewTo describe inherited and acquired genetic variants and clinical entities associated with increased basal serum tryptase (BST), distinguish these levels from those which acutely rise due to mast cell activation, and finally to characterize the association between chronically elevated basal serum tryptase and episodic mast cell activation.Recent FindingsHereditary alpha-tryptasemia is a commonly inherited genetic cause for basally elevated serum tryptase and explains elevated BST in many individuals who do not have evidence of clonal myeloid or mast cell disease. When clonal myeloid disease is present, BST may be elevated and can be a biomarker of a number of disparate disorders of the myeloid compartment.SummaryElevated BST is most commonly caused by hereditary alpha tryptasemia but may also be indicative of clonal myeloid disease. Clinical reports suggest that elevated BST is associated with increased risk for more severe systemic allergic reactions to a number of eliciting agents and exposures. Additional studies are needed to determine the role that inherited or acquired genetic variants associated with elevated BST and clonal or non-clonal myeloid diseases may play in these reactions.
Journal Article
ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition)
The clinical multifocal electroretinogram (mfERG) is an electrophysiological test of local retinal function. With this technique, many local ERG responses are recorded quasi-simultaneously from the cone-driven retina under light-adapted conditions. This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV:
www.iscev.org
), replaces the ISCEV guidelines for the mfERG published in 2007. Standards for performance of the basic clinical mfERG test with a stimulus array of 61 or 103 hexagons, as well as for reporting the results, are specified.
Journal Article