Uric acid disrupts hypochlorous acid production and the bactericidal activity of HL-60 cells.

Uric acid is the end product of purine metabolism in humans and is an alternative physiological substrate for myeloperoxidase. Oxidation of uric acid by this enzyme generates uric acid free radical and urate hydroperoxide, a strong oxidant and potentially bactericide agent. In this study, we investigated whether the oxidation of uric acid and production of urate hydroperoxide would affect the killing activity of HL-60 cells differentiated into neutrophil-like cells (dHL-60) against a highly virulent strain (PA14) of the opportunistic pathogen Pseudomonas aeruginosa. While bacterial cell counts decrease due to dHL-60 killing, incubation with uric acid inhibits this activity, also decreasing the release of the inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF- α). In a myeloperoxidase/Cl-/H2O2 cell-free system, uric acid inhibited the production of HOCl and bacterial killing. Fluorescence microscopy showed that uric acid also decreased the levels of HOCl produced by dHL-60 cells, while significantly increased superoxide production. Uric acid did not alter the overall oxidative status of dHL-60 cells as measured by the ratio of reduced (GSH) and oxidized (GSSG) glutathione. Our data show that uric acid impairs the killing activity of dHL-60 cells likely by competing with chloride by myeloperoxidase catalysis, decreasing HOCl production. Despite diminishing HOCl, uric acid probably stimulates the formation of other oxidants, maintaining the overall oxidative status of the cells. Altogether, our results demonstrated that HOCl is, indeed, the main relevant oxidant against bacteria and deviation of myeloperoxidase activity to produce other oxidants hampers dHL-60 killing activity.

Double hit lymphoma: from biology to therapeutic implications.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous disease defined by different cellular origins and mechanisms of oncogenic activation. Approximately 10% of DLBCL cases harbor a MYC rearrangement and this has been associated with a more aggressive clinical course following standard therapy. AREAS COVERED: So-called 'double-hit lymphomas' (DHL) or 'triple hit lymphomas' (THL) occur when MYC is concurrently rearranged with BCL2 and/or BCL6. These tumors are characterized by high proliferation rate and a very poor outcome following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin vincristine and prednisone) therapy, in most (though not all) studies that have looked at this. Though there is a paucity of published experience with other chemotherapy regimens, there is emerging evidence that more intensive approaches may improve outcome. Recently, there has been a lot of focus in the literature on 'double-expresser lymphomas' (DEL) with high MYC, BCL2 and/or BCL6 expression but typically without rearrangements of these genes. These DEL cases, have a poor outcome with R-CHOP and there is little consensus on how they should be approached. Expert commentary: This review will focus on the biology and treatment of DHL and DEL, discuss the outcome of these diseases with current standard as well as promising new approaches and conclude with a section on novel agents that are in development for these diseases.

Concentrações de creatino quinase, aspartato aminotransferase e desidrogenase lática em potros do nascimento até os seis meses de idade

Ten Thoroughbred foals, male and female, had the seric concentration of creatine kinase (CK), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) determined. Blood samples were collected every day from days 1 to 7 and on days 15, 30, 60, 90, 120, 150 and 180 of age. CK activity decreased significantly (p 0.0003) in the first week and showed significant variation between day 15 and 6 months of age. AST showed a significant (p 0.0001) increase in its values until 102 days of age, decreasing subsequently until 6 months of age. LDH values decreased significantly (p 0.0002) between days 15 and 120, increasing subsequently until 6 months of age. At 6 months of age CK, AST and LDH activities were close to those of adult horses.

Dez potros da raça Puro Sangue de Corrida (PSC), de ambos os sexos, foram avaliados quanto à concentração das enzimas séricas creatino quinase (CK), aspartato aminotransferase (AST) e deshidrogenase lática (DHL). Foram colhidas amostras sangüíneas diariamente do 1º ao 7ºdia de vida e depois aos 15, 30, 60, 90, 120, 150 e 180 dias de idade. A concentração da CK mostrou um decréscimo significativo (p 0,0003) do1º ao 7º dia de idade, e variação também significativa (p 0,0044) entre o 15º dia de vida até os seis meses. A AST apresentou elevação significativa (p 0,0001) até os 102 dias de idade, sofrendo posterior declínio até o 6º mês. A DHL apresentou decréscimo significativo (p 0,0002) nas suas concentrações entre os 15 e 120 dias de idade, com posterior elevação até o 6º mês. Aos seis meses de idade as concentrações séricas de CK, AST e DHL, estão próximas as de eqüinos adultos.

Concentrações de creatino quinase, aspartato aminotransferase e desidrogenase lática em potros do nascimento até os seis meses de idade

Ten Thoroughbred foals, male and female, had the seric concentration of creatine kinase (CK), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) determined. Blood samples were collected every day from days 1 to 7 and on days 15, 30, 60, 90, 120, 150 and 180 of age. CK activity decreased significantly (p 0.0003) in the first week and showed significant variation between day 15 and 6 months of age. AST showed a significant (p 0.0001) increase in its values until 102 days of age, decreasing subsequently until 6 months of age. LDH values decreased significantly (p 0.0002) between days 15 and 120, increasing subsequently until 6 months of age. At 6 months of age CK, AST and LDH activities were close to those of adult horses.

Dez potros da raça Puro Sangue de Corrida (PSC), de ambos os sexos, foram avaliados quanto à concentração das enzimas séricas creatino quinase (CK), aspartato aminotransferase (AST) e deshidrogenase lática (DHL). Foram colhidas amostras sangüíneas diariamente do 1º ao 7ºdia de vida e depois aos 15, 30, 60, 90, 120, 150 e 180 dias de idade. A concentração da CK mostrou um decréscimo significativo (p 0,0003) do1º ao 7º dia de idade, e variação também significativa (p 0,0044) entre o 15º dia de vida até os seis meses. A AST apresentou elevação significativa (p 0,0001) até os 102 dias de idade, sofrendo posterior declínio até o 6º mês. A DHL apresentou decréscimo significativo (p 0,0002) nas suas concentrações entre os 15 e 120 dias de idade, com posterior elevação até o 6º mês. Aos seis meses de idade as concentrações séricas de CK, AST e DHL, estão próximas as de eqüinos adultos.