Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described carboxypeptidase that is potentially involved in the regulation of fibrinolysis by decreasing plasminogen binding to the fibrin surface. This role makes the TAFI gene a good candidate in atherothrombotic diseases. The great interindividual variability of plasma TAFI antigen levels is poorly explained by lifestyle characteristics, thus suggesting its genetic determination. To test this hypothesis, the promoter and the 3-untranslated region of the TAFI gene were screened for polymorphisms, and their contribution to the variability of plasma TAFI antigen levels was evaluated. Seven new polymorphisms are described, 5 in the promoter (C-2599G, ؊2345 2G/1G, A-1690G, G-1102T, and G-438A) and 2 in the 3UTR (C؉1542G and T؉1583A). All these polymorphisms were in strong linkage disequilibrium with each other and with the previously described Ala147Thr polymorphism. They generated 4 main haplotypes, accounting for 80% of all observed haplotypes. In univariate analyses, all polymorphisms were associated with plasma TAFI Ag levels and, individually, contributed to a large fraction of plasma TAFI Ag levels, ranging from 20% to 52%. In a stepwise regression analysis including all polymorphisms, several combinations remained significantly and independently associated with plasma TAFI Ag levels: C؉1542G associated with Ala147Thr, T؉1583A, or ؊2345 2G/1G explaining 61.6%, 60.2%, and 58.1% of the variance, respectively. These findings clearly demonstrate that circulating levels of TAFI are strongly determined by polymorphic variations in the promoter and the 3UTR of the TAFI gene. (Blood. 2001;97:2053-2058

Abstract-The thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis that decreases plasminogen binding to the fibrin surface. The plasma TAFI concentration is almost entirely genetically determined. We investigated whether plasma TAFI levels and polymorphisms located in the TAFI gene could constitute risk markers of myocardial infarction (MI). Plasma TAFI antigen (Ag) levels were assayed by ELISA and 2 TAFI gene polymorphisms (Ala147Thr and Cϩ1542G in the 3Ј untranslated region) were determined in a large European case-control study. This study compared 598 men recruited 3 to 6 months after MI with 653 age-matched controls from North Europe (Stockholm, Sweden, and London, England) and South Europe (Marseilles, France, and San Giovanni Rotondo, Italy). A TAFI Ag value above the 90th percentile was associated with a significantly lower risk of MI (odds ratio 0.55, PϽ0.02), indicating that elevated TAFI may be protective against MI. As previously shown, the 2 TAFI gene polymorphisms were in strong linkage disequilibrium and were associated with the TAFI Ag concentration, with carriers of the Thr147 and 1542C alleles having higher levels (PϽ0.0005). These effects were similar in controls and cases and in each center. There was a difference in allele frequency between cases and controls for the Ala147Thr polymorphism, with Thr147 allele carriers being more frequent in controls than in cases in 2 centers, Stockholm (Pϭ0.03) and San Giovanni Rotondo (Pϭ0.03); the odds ratio for the entire cohort was 0.78 (PϽ0.05). In conclusion, patients with a recent MI presented lower values of TAFI Ag and higher frequencies of the "TAFI-decreasing" alleles. The geographical differences observed do not contribute to explaining the North-South gradient in MI risk in Europe. Key Words: thrombin-activatable fibrinolysis inhibitors Ⅲ myocardial infarction Ⅲ genetic polymorphisms Ⅲ fibrinolysis T he thrombin-activatable fibrinolysis inhibitor (TAFI), also known as procarboxypeptidase B and procarboxypeptidase U, has been recently described. 1-3 It can potently inhibit fibrinolysis by removing carboxy-terminal lysine residues from partially degraded fibrin, decreasing plasminogen binding on its surface. 4 -7 Because of its role in the fibrinolytic system, TAFI may be implicated in atherothrombotic diseases. Studies conducted in different animal models support a physiological role of TAFI in the regulation of fibrinolysis. 8 -11 In humans, van Tilburg et al, 12 have shown that an increased plasma TAFI antigen (Ag) concentration could be a risk marker for venous thrombosis. 12 In a pilot study of men with stable angina pectoris and angiographically verified coronary artery disease, it was found that the plasma levels of TAFI were significantly higher in the patients than in healthy population-based age-matched men. 13 The between-individual differences in plasma TAFI concentration are only partly explained by environmental factors, suggesting a strong influence of genetic factors. 14,15 The hum...

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11R183C and GNA11Q209L in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11R183C under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.

The TOPICOP score can be feasibly applied across countries and may therefore be useful for obtaining qualitative and quantitative data from international studies and for adapting patient education and treatment.

© F e r r a t a S t o r t i F o u n d a t i o neral T-cell lymphomas (PTCL) but mainly in angioimmunoblastic T-cell lymphoma (AITL). [14][15][16][17][18] PTCLs have also been reported during CD3-CD4 + L-HES course. 6,9,[19][20][21][22][23][24] Two of 23 patients currently followed in the French Eosinophil Network, and one more patient recently reported by others, 25 developed well-defined AITL several years after L-HES diagnosis, which thus raised the problem of the diagnosis of well-defined T-cell lymphoma in patients who have clonal circulating T cells.In this study, we focused on the lymphoid infiltrates in lymph nodes, skin and other available biopsies of tissue involved in L-HES, to assess the presence of clonal T cells at diagnosis and during CD3 - CD4+ L-HES course. We secondly aimed to distinguish L-HES from AITL by comparing histopathological and immunophenotypic characteristics between both entities Methods PatientsTwenty-three hypereosinophilic syndrome (HES) patients with a documented presence of CD3 - CD4+ aberrant subset and a negative FIP1L1-PDGFRA fusion gene research are currently followed The clonal T-cell disease in CD3 -CD4 + L-HES haematologica | 2015; 100(8) 1087 © F e r r a t a S t o r t i F o u n d a t i o nSkin lesions in L-HES patients were pruritic papulo-nodular inpatients P1 and P2, pruritic papular lesions in patient P3, P5, P8, isolated pruritus in patients P7 and P9. Numbers in in the French Eosinophil Network. For the present study, 16 patients (P1-P16) were included, 12 of them had available tissue biopsies during L-HES course. All satisfied criteria for HES (n=15) or hypereosinophilia (HE) (n=1, P13, no organ damage or clinical manifestation) criteria in accordance with the latest up-dated consensus definitions.1 Main clinical characteristics are summarized in Table 1. For the 7 remaining patients, no complementary lymphocyte immunophenotyping was performed, no biopsy was performed (n=5) or biopsies were not available for analysis (n=2). The study was approved by the Lille Hospital Ethical Committee and carried out in accordance with the Declaration of Helsinki.Ten of these patients had bone marrow biopsies at CD3 -CD4 + L-HES diagnosis in order to exclude a T-cell lymphoma (Patients P2-4, P8, P9, P11, P12, P14-16) (data not shown). Four patients had lymph nodes biopsies for a suspicion of T-cell lymphoma during follow up (Patients P1, P3, P4 and P10). For this work, all their biopsies were retrieved for further investigation and for a centralized compared analysis to be made.Finally, Patients P4 and P16 developed a well-defined AITL during L-HES course (AITL/L-HES patients).Patient P4. Patient P4 was 18-years old when a CD3 -CD4 + L-HES diagnosis was made in 1999 and was previously reported by us. 26He presented with eczema-like lesions, rare episodes of angioedema and multiple adenopathy. Despite high circulating CD3 -CD4 + T-cell count (28 G/L), lymph node histological examination confirmed lymphoid reactive hyperplasia. As he was in really good G. Lefèvre ...

The CD3-CD4+ aberrant T-cell phenotype is the most described in the lymphoid variant of hypereosinophilic syndrome (L-HES), a rare form of HES. Only a few cases have been reported, and data for these patients are scarce. To describe characteristics and outcome of CD3-CD4+ L-HES patients, we conducted a national multicentric retrospective study in the French Eosinophil Network. All patients who met the recent criteria of hypereosinophilia (HE) or HES and who had a persistent CD3-CD4+ T-cell subset on blood T-cell phenotyping were included. Clinical and laboratory data were retrospectively collected by chart review. CD3-CD4+ L-HES was diagnosed in 21 patients (13 females, median age 42 years [range, 5–75 yr]). Half (48%) had a history of atopic manifestations. Clinical manifestations were dermatologic (81%), superficial adenopathy (62%), rheumatologic (29%), gastrointestinal (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). The median absolute CD3-CD4+ T-cell count was 0.35 G/L (range, 0.01–28.3), with a clonal TCRγδ rearrangement in 76% of patients. The mean follow-up duration after HES diagnosis was 6.9 ± 5.1 years. All patients treated with oral corticosteroids (CS) (n = 18) obtained remission, but 16 required CS-sparing treatments. One patient had a T-cell lymphoma 8 years after diagnosis, and 3 deaths occurred during follow-up.In conclusion, clinical manifestations related to CD3-CD4+ T cell-associated L-HES are not limited to skin, and can involve all tissue or organs affected in other types of HE. Contrary to FIP1L1-PDGFRA chronic eosinophilic leukemia patients, CS are always effective in these patients, but CS-sparing treatments are frequently needed. The occurrence of T-cell lymphoma, although rare in our cohort, remains a major concern during follow-up.

Summary. Increased plasma thrombin-activatable ®brinolysis inhibitor (TAFI) levels were recently shown to be a part of the insulin resistance syndrome. We investigated the relationship between plasma TAFI antigen levels and insulin resistance markers and compared these results with those obtained for PAI-1 and ®brinogen which are known to be closely related to insulin resistance syndrome and fat mass, respectively. Eightynine obese females had 1.3-, 1.2-, and 3-fold higher circulating TAFI, ®brinogen and PAI-1, respectively, compared with 64 lean females. Univariate analysis showed that the signi®cance level for association between TAFI or ®brinogen concentrations and insulin resistance markers was lower than the signi®cance level for association between PAI-1 and insulin resistance markers. Nevertheless, TAFI, ®brinogen, and PAI-1 plasma levels were signi®cantly associated to each other. In linear stepwise ascendant analysis, insulin resistance markers accounted for 50% of the interindividual variability of plasma PAI-1 and only for 10% of plasma TAFI and 13% of ®brinogen variability. The contribution of insulin resistance markers to plasma TAFI antigen levels variability disappeared when PAI-1 or ®brinogen was entered in the statistical model. TAFI mRNA was detected in the liver but not in adipose tissue and endothelial cells. No TAFI mRNA was detected in normal or atherosclerotic vessels either. These results suggest that elevated TAFI antigen levels found in obese subjects are not independently associated with the metabolic markers of the insulin resistance syndrome. Increased plasma TAFI antigen levels in obesity might re¯ect a speci®c pathway of regulation at the liver level.

Summary Backround Propranolol is now widely used to treat severe infantile haemangiomas (IHs). Very few cases of propranolol‐resistant IH (PRIH) are mentioned in the literature. Objectives To describe the characteristics of PRIHs. Methods A national, multicentre, retrospective, observational study was conducted from February 2011 to December 2011. All patients with PRIH evaluated by the members of the Groupe de Recherche Clinique en Dermatologie Pédiatrique from 1 January 2007 to 1 December 2011 were eligible. Results Among 1130 patients treated with propranolol for infantile haemangioma, 10 (0·9%) had PRIHs. Haemangioma propranolol resistance was observed at all ages during early childhood and at any proliferation stage. Conclusions PRIH is a rare phenomenon that raises questions and merits further investigation.