The treatment of polycythaemia vera: an update in the JAK2 era

The clinical course of polycythaemia vera is marked by a high incidence of thrombotic complications, which represent the main cause of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use raises the risk of transformation into acute leukaemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients should be treated with phlebotomy and low-dose aspirin. Cytotoxic therapy is indicated in high-risk patients, with the drug of choice being hydroxyurea because its leukaemogenicity is low. The recent discovery of JAK2 V617F mutation in the vast majority of polycythaemia vera patients opens new avenues for the treatment of this disease. Novel therapeutic options theoretically devoid of leukaemic risk, such as alpha-interferon and imatinib, affect JAK2 expression in some patients. Nevertheless, these drugs require further clinical experience and, for the time being, should be reserved for selected cases

Treatment of venous thromboembolism with low-molecular-weight heparin: a synthesis of the evidence published in systematic literature reviews

Objective: To evaluate the methodology and cumulative evidence presented in systematic reviews of clinical trials comparing low-molecular-weight heparin (LMWH) with unfractionated heparin (UFH) for the treatment of venous thromboembolism. Methods: We reviewed all systematic reviews of clinical trials published until March 2002. Fourteen systematic literature reviews were published between 1994 and 2000. Deficiencies in methodological quality were common, particularly in the description of search strategies, assessment of clinical trial quality, and methods used to combine results. Results: Results of reviews indicate that LMWH is superior to UFH for the treatment of venous thromboembolism, particularly in reducing mortality. Patients with isolated deep venous thrombosis or deep venous thrombosis with concomitant pulmonary embolism seemed to have similar benefit. However, the benefits of LMWH over UFH were smaller in magnitude in reviews that included more recent clinical trials

Exploring the substrate specificities of α-2,6- and α-2,3-sialyltransferases using synthetic acceptor analogues

The acceptor specificities of rat liver Gal(β1-4)GlcNAc α-2,6-sialyltransferase, recombinant fulllength human liver Gal(β1-4)GlcNAc α-2,6-sialyltransferase, and a soluble form of recombinant rat liver Gal(β1-3/4)GlcNAc α2,3-sialyltransferase were studied with a panel of analogues of the trisaccharide Gal(β1-4)GlcNAc(βl-2)Man(α1-O)(CH2)7CH3. These analogues contain structural variants of D-galactose, modified at either C3, C4 or C5 by deoxygenation, fluorination, O-methylation, epimerization, or by the introduction of an amino group. In addition, the enantiomer of D-galactose is included. The α-2,6-sialyltransferases tolerated most of the modifications at the galactose residue to some extent, whereas the α-2,3-sialyltransferase displayed a narrower specificity. Molecular dynamics simulations were performed in order to correlate enzymatic activity to three-dimensional structure. Ineffective acceptors for rat liver α-2,6-sialyltransferase were shown to be inhibitory towards the enzyme; likewise, the α-2,3-sialyltransferase was found to be inhibited by all non-substrates. Modified sialyloligosaccharides were obtained on a milligram scale by incubation of effective acceptors with one of each of the three enzymes, and characterized by 500-MHz 1H-NMR spectroscopy