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JAK2 617V>F mutation occurs in a homozygous state in 25% to 30% of patients with polycythemia vera (PV) and 2% to 4% with essential thrombocythemia (ET IntroductionPatients with Philadelphia-negative chronic myeloproliferative disorders (CMPDs) 1 harbor a recurrent mutation in the Janus tyrosine kinase 2 (JAK2) gene, consisting of a valine-tophenylalanine change at position 617 (JAK2 617VϾF) in the JH2 pseudo-kinase domain. [2][3][4][5] The JAK2 617VϾF mutation is present in the vast majority of patients with polycythemia vera (PV) 2-5 and in 40% to 60% of those with essential thrombocythemia (ET) 6-8 or myelofibrosis with myeloid metaplasia (MMM). 9,10 JAK2 617VϾF can also occasionally be detected in "atypical" MPD, myelodysplastic syndromes, chronic myelomonocytic leukemia, systemic mastocytosis, chronic neutrophilic leukemia, and eosinophilic disorders. 11-13 Mutant JAK2 is a constitutively active tyrosine kinase that confers growth factor independence in transfected hematopoietic cell lines [2][3][4][5] and is at the basis of the phenomenon of erythropoietin-independent erythroid colony (EEC) growth that is a hallmark of most PV patients and is also less frequently reported in patients with ET. 14 A key role for the "gain-of-function" 15 of mutated JAK2 in the pathogenesis of CMPD is supported by in vitro studies, which showed enhanced JAK-STAT signaling in cells bearing the mutant allele, and by in vivo animal models in which erythrocytosis 3,16 and eventually myelofibrosis 16,17 developed following transplantation of hematopoietic cells transfected with mutant JAK2 into mice.About 25% to 30% of PV and MMM patients, and 2% to 4% of ET patients, harbor the mutation in the homozygous state, a condition where at least 51% of JAK2 alleles in granulocytes are mutated as the result of a mitotic recombination process. 2-5 While a consistent number of reports have investigated the impact of the presence of 617VϾF mutation per se on the clinical and hematologic profile of CMPD patients, a few studies have specifically addressed the consequences of JAK2 617VϾF mutation when harbored in the homozygous state. 18 The complete loss of normal JAK2 allele is expected to have profound effects on cell phenotype. As a matter of fact, in cotransfection experiments, the wild-type

on behalf of the GISSI-Prevenzione InvestigatorsBackground-Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (Ͻ3 months) myocardial infarction. Methods and Results-In this study, 11 323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; Pϭ0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; Pϭ0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths. Conclusions-The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.

To assess the clinical significance of lupus anticoagulants (LAs) and antiphospholipid antibodies (aPLs) toward thrombosis and abortions, we measured them in 112 patients whose samples were available at enrollment in the warfarin in the antiphospholipid syndrome (WAPS) study. Enzyme-linked immunosorbent assay (ELISA) and coagulation test values in the highest and lowest tertiles were compared. When considered separately, IgG antibodies to ␤2-glycoprotein I (a␤2GPI) and prothrombin (aPT) were associated with anamnestic arterial and venous thrombosis, respectively, and those to annexin AV (aAnAV) with abortions. IgM antibodies to protein S and the lupus ratio of the dilute prothrombin time were associated with prospective thrombosis. No other association for IgM antibodies was seen. LA-positive patients who carried a␤2GPI antibodies were at risk of anamnestic arterial and total thrombosis and aPT antibodies to that of anamnestic venous and total thrombosis. LA-positive patients who carried IgG a␤2GPI and aAnAV antibodies were at risk for both anamnestic abortion and prospective thrombosis. Overall, these data support the inclusion of a␤2GPI antibodies in and suggest the removal of anticardiolipin antibodies from the laboratory criteria of the antiphospholipid syndrome. They also suggest that the measurement of aPT and aAnAV antibodies is useful in some selected situations and that there is little role for IgM antibody detection. (Blood.