Rigid surface operators and S-duality: some proposals

We study surface operators in the N=4 supersymmetric Yang-Mills theories with gauge groups SO(n) and Sp(2n). As recently shown by Gukov and Witten these theories have a class of rigid surface operators which are expected to be related by S-duality. The rigid surface operators are of two types, unipotent and semisimple. We make explicit proposals for how the S-duality map should act on unipotent surface operators. We also discuss semisimple surface operators and make some proposals for certain subclasses of such operators.Comment: 27 pages. v2: minor changes, added referenc

Severe thrombophilia in a factor V‐deficient patient homozygous for the Ala2086Asp mutation (FV Besançon)

International audienceBackground Coagulation factor V (FV), present in plasma and platelets, has both pro- and anticoagulant functions.Objective We investigated an FV-deficient patient (FV:C 3%, FV:Ag 4%) paradoxically presenting with recurrent venous thrombosis (11 events) instead of bleeding.Methods/Results Thrombophilia screening revealed only heterozygosity for the F2 20210G>A mutation. Although thrombin generation in the patient's platelet-poor plasma was suggestive of a hypocoagulable state, thrombin generation in the patient's platelet-rich plasma (PRP) was higher than in control PRP and extremely resistant to activated protein C (APC). This was partially attributable to the complete abolition of the APC-cofactor activity of FV and a marked reduction of plasma tissue factor pathway inhibitor antigen and activity. The patient was homozygous for a novel missense mutation (Ala2086Asp, FVBesancon) that favors a "closed conformation" of the C2 domain, predicting impaired binding of FV(a) to phospholipids. Recombinant FVBesancon was hardly secreted, indicating that this mutation is responsible for the patient's FV deficiency. Model system experiments performed using highly diluted plasma as a source of FV showed that, compared with normal FVa, FVa(Besancon) has slightly (<= 1.5-fold) unfavorable kinetic parameters (K-m, V-max) of prothrombin activation, but also a lower rate of APC-catalyzed inactivation in the presence of protein S.Conclusions FVBesancon induces a hypercoagulable state via quantitative (markedly decreased FV level) and qualitative (phospholipid-binding defect) effects that affect anticoagulant pathways (anticoagulant activities of FV, FVa inactivation, tissue factor pathway inhibitor alpha level) more strongly than the prothrombinase activity of FVa. A possible specific role of platelet FV cannot be excluded

Laboratory Techniques Used to Diagnose Constitutional Platelet Dysfunction

International audiencePlatelets play a major role in primary hemostasis, where activated platelets form plugs to stop hemorrhaging in response to vessel injuries. Defects in any step of the platelet activation process can cause a variety of platelet dysfunction conditions associated with bleeding. To make an accurate diagnosis, constitutional platelet dysfunction (CPDF) should be considered once von Willebrand disease and drug intake are ruled out. CPDF may be associated with thrombocytopenia or a genetic syndrome. CPDF diagnosis is complex, as no single test enables the analysis of all aspects of platelet function. Furthermore, the available tests lack standardization, and repeat tests must be performed in specialized laboratories especially for mild and moderate forms of the disease. In this review, we provide an overview of the laboratory tests used to diagnose CPDF, with a focus on light transmission platelet aggregation (LTA), flow cytometry (FC), and granules assessment. Global tests, mainly represented by LTA, are often initially performed to investigate the consequences of platelet activation on platelet aggregation in a single step. Global test results should be confirmed by additional analytical tests. FC represents an accurate, simple, and reliable test to analyze abnormalities in platelet receptors, and granule content and release. This technique may also be used to investigate platelet function by comparing resting- and activated-state platelet populations. Assessment of granule content and release also requires additional specialized analytical tests. High-throughput sequencing has become increasingly useful to diagnose CPDF. Advanced tests or external research laboratory techniques may also be beneficial in some cases

Genetic predictors of response to photodynamic therapy

In Western countries, therapeutic management of patients affected by choroidal neovascularization (CNV) secondary to different typologies of macular degeneration represents a major health care problem. Age-related macular degeneration is the disease most frequently associated with CNV development. Schematically, CNVs can be distinguished into classic and occult subtypes, which are characterized by variable natural history and different responsiveness to some therapeutic procedures. At present, the dramatic vision loss due to CNV can be mainly treated by two interventional strategies, which are utilizable in either single or combined modalities: photodynamic therapy with verteporfin (PDT-V), and intravitreal administration of drugs acting against vascular endothelial growth factor. The combined use of PDT-V and anti-angiogenic drugs represents one of the most promising strategies against neovascular macular degeneration, but it unavoidably results in an expensive increase in health resource utilization. However, the positive data from several studies serve as a basis for reconsidering the role of PDT-V, which has undergone a renaissance prompted by the need for a more rational therapeutic approach toward CNV. New pharmacogenetic knowledge of PDT-V points to exploratory prospects to optimize the clinical application of this intriguing photothrombotic procedure. In fact, a Medline search provides data regarding the role of several single nucleotide polymorphisms (SNPs) as genetic predictors of CNV responsiveness to PDT-V. Specifically, correlations between SNPs and different levels of PDT-V efficacy have been detected by examining the gene variants influencing (i) thrombo-coagulative pathways, i.e. methylenetetrahydrofolate reductase (MTHFR) 677C>T (rs1801133), factor V (F5) 1691G>A (rs6025), prothrombin (F2) 20210G>A (rs1799963), and factor XIII-A (F13A1) 185G>T (rs5985); (ii) complement activation and/or inflammatory processes, i.e. complement factor H (CFH) 1277T>C (rs1061170), high-temperature requirement factor A1 (HTRA1) promoter -512G>A (rs11200638), and two variants of the C-reactive protein (CRP) gene (rs2808635 and rs876538); and (iii) production and bioavailability of vascular endothelial growth factor (VEGFA -2578C>A [rs699947] and rs2146323). This article critically evaluates both the clinical plausibility and the opportunity to utilize the most important SNP-response interactions of PDT-V for an effective upgrade of the current anti-CNV therapeutic scenario. In addition, the pharmacogenetics of a very severe post-PDT-V adverse event, i.e. a decrease in acute vision, is briefly discussed. A comprehensive appraisal of the findings reviewed in this article should be carefully considered to design future trials aimed at verifying (after proper genotypic stratification of the enrolled patients) whether these innovative pharmacogenetic approaches will be able to improve the multifaceted interventional management of neovascular macular degeneration