Patients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability is largely genetically determined, and it can be only partly explained by genetic variability in the cytochrome CYP2C9 locus. In 147 patients followed from the start of anticoagulation with warfarin, we have investigated whether VKORC1 gene mutations have affected doses of drug prescribed to acquire the target anticoagulation intensity. Two synonymous mutations, 129C>T at Cys43 and 3462C>T at Leu120, and 2 missense mutations, Asp38Tyr and Arg151Gln, were identified. None of these mutations was found to affect the interindividual variability of warfarin prescribed. Finally, 2 common polymorphisms were found, 1173C>T in the intron 1 and 3730G>A transition in the 3 untranslated region (UTR). Regardless of the presence of confounding variables, the mean adjusted dose required of warfarin was higher (6.2 mg) among patients with the VKORC1 1173CC genotype than those of patients carrying the CT (4.8 mg; P ‫؍‬ .002) or the TT genotype (3.5 mg; P < .001). In the present setting, VKORC1 and CYP2C9 genetic variants investigated accounted for about a third (r 2 , 0.353)

. Cell death and the subsequent post-mortem changes, called necrosis, are integral parts of normal development and maturation cycle. Despite the importance of this process, the mechanisms underlying cell death are still poorly understood. In the recent literature, cell death is said to occur by two alternative, opposite modes: apoptosis, a programmed, managed form of cell death, and necrosis, an unordered and accidental form of cellular dying. The incorrect consequence is the overlapping of: a) the process whereby cells die, cell death; and b) the changes that the cells and tissues undergo after the cells die. Only the latter process can be referred to as necrosis and represents a 'no return' process in cell life. In this review, we discuss the excellent basic research developed in this field during last decades and problems that remain to be resolved in defining both experimentally and mechanicistically the events that lead to and characterize cell death. IntroductionCell death is part of normal development and maturation cycle, and is the component of many response patterns of living tissues to xenobiotic agents (i.e. micro organisms and chemicals) and to endogenous modulations, such as inflammation and disturbed blood supply (1,2). Cell death is an important variable in cancer development, cancer prevention and cancer therapy (3-5). In the treatment of cancer, the major approach is the removal, by surgery, of the neoplasm and/or the induction of cell death in neoplastic cells by radiation, toxic chemicals, antibodies and/or cells of the immune system (6-9). On the other hand, this pathobiological process remains poorly understood and the physiological and biochemical factors that lead to cell death are still not clear. One main factor is the existing confusion between 'apoptosis' process, as compared and contrasted with 'necrosis', leading to the overlapping of the ante mortem changes, i.e. the process of cell death, and the post-mortem changes, i.e. the necrosis process. The pathobiology of cell deathThe elegant scientific exploration of sub-cellular molecular anatomy of the last decades have reinforced the cell concept as 'the smallest integrating unit in biology: a pseudo-intelligent computer that receives, screens, changes, reacts to and adapts to a host of environmental signals, all of this activity apparently

ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE.

BackgroundThe high mutational heterogeneity of hemophilia A is a challenge for the provision of genetic services. We plan to identify the mutation in patients with hemophilia A in order to create a confidential national database of mutations for the optimization of genetic services in Italy.