Association between Lp-PLA2 and coronary artery disease: focus on its relationship with lipoproteins and markers of inflammation and hemostasis

Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates pro-inflammatory molecules from oxidized LDL. We examined the association between Lp-PLA2 plasma concentrations and risk of stable coronary artery disease (CAD) in a large case-control study and further assessed the relationship between Lp-PLA2 and various lipid, inflammatory and hemostatic parameters. Lp-PLA2 concentrations were measured in 312 patients with CAD and in 479 age- and gender-matched blood donors. Various sensitive inflammatory and hemostatic markers and a complete lipoprotein profile were obtained. Lp-PLA2 concentrations were significantly higher in cases than in controls (296.1 ng/mL versus 266.0 ng/mL, p<0.0001). In multivariable logistic regression, the age- and gender-adjusted OR for the presence of CAD was 1.61 (95% CI, 1.07-2.44) if the top quartile of the Lp-PLA2 distribution was compared to the bottom quartile. Adjustment for traditional cardiovascular risk factors and statin use resulted in an OR of 2.04 (95% CI, 1.19-3.48). After additional controlling for vWF, the OR was slightly attenuated but still remained statistically significant (OR 1.91; 95% CI, 1.12-3.28). Thus, elevated Lp-PLA2 concentrations were associated with the presence of stable CAD, independent of various biochemical markers. Our results support the hypothesis that Lp-PLA2 may be a novel, independent risk marker for CAD.     

Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial

Risk assessment in acute myeloid leukemia (AML) using pretreatment characteristics may be improved by incorporating parameters of early response to therapy. In the 1992 trial of the German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449 patients 16 to 76 years of age (median, 53 years) with de novo AML entered the trial and were evaluable. Treatment included TAD/HAM (thioguanine, cytosine arabinoside, and daunorubicin/high-dose cytosine arabinoside and mitoxantrone) double induction, TAD consolidation, and randomly either maintenance therapy or S-HAM consolidation. Cytogenetics were favorable, intermediate, unfavorable and not available in 10.0%, 48.3%, 13.1%, and 28.5%, respectively. Day 16 blasts ranged from 0% to 100% (median, 5%, mean +/- SD, 18.6 +/- 28.5%). Complete remission (CR) rate was 72.6%, 17.6% had persistent leukemia (PL), and 9.8% succumbed to hypoplastic death. Median overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were 18, 9, and 15 months with 28.4%, 21.6%, and 30.1% at 5 years, respectively. As a continuous variable, day 16 blasts were related to CR rate (P < 0.0001), PL rate (P < 0.0001), OS (P < 0.0001), EFS (P < 0.0001), and RFS (P = 0.0049). Multivariate analyses identified the following parameters to be associated with the respective end points. CR rate: day 16 blasts (P <.0001), age (P =.0036), and LDH (P =.0072); OS: unfavorable cytogenetics (P <.0001), day 16 blasts (P <.0001), age (P <.0001), and LDH (P =.0040); EFS: unfavorable cytogenetics (P <.0001), LDH (P <.0001), day 16 blasts (P <.0001), and age (P =.0061); RFS: unfavorable cytogenetics (P <.0001), LDH (P <.0001), and day 16 blasts (P =.0359). The prognostic significance of day 16 blasts is independent of pretherapeutic parameters and predicts outcome even in patients achieving a CR.     

“Distressed aging”: the differences in brain activity between early- and late-onset tinnitus

Recent findings regarding different characteristics according to the age of tinnitus onset prompted us to conduct a study on the differences in tinnitus-related neural correlates between late-onset tinnitus (LOT; mean onset age, 60.4 years) and early-onset tinnitus (EOT; mean onset age, 29.7 years) groups. Hence, we collected quantitative electroencephalography findings of 29 participants with LOT and 30 with EOT, and from 59 controls. We then compared the results between the 2 groups and between the tinnitus groups and age- and sex-matched control groups using resting state electroencephalography source-localized activity and connectivity analyses. Compared with the EOT and older control groups, the LOT group demonstrated increased localized activity and functional connectivity in components of previously described tinnitus distress networks, and the default mode and intrinsic alertness networks, such as the prefrontal cortices, dorsal anterior cingulate cortex, and insula. The current findings of intrinsic differences in tinnitus-related neural activity between the LOT and EOT groups might be applicable for planning individualized treatment modalities according to age of onset. Moreover, differences with regard to the age of tinnitus onset might be a milestone for future studies on onset-related differences in other similar pathologies, such as pain or depression.     

Histone methyltransferase Suv39h1 deficiency prevents Myc‐induced chromosomal instability in murine myeloid leukemias

Suv39h1 mediates heterochromatin formation in pericentric and telomeric regions by trimethylation of lysine 9 of histone 3 (H3K9me3). Yet, its role in the induction of chromosomal instability is poorly understood. We established a leukemia model by retrovirally expressing Myc in wild‐type and histone methyltransferase Suv39h1‐deficient hematopoietic cells and characterized the resulting leukemias for chromosomal instability. All mice that received cells overexpressing Myc developed myeloid leukemia with a median survival of 44 days posttransplantation. Myc‐overexpressing wild‐type leukemias demonstrated clones with numerical chromosomal aberrations (5/16). In secondary transplantations of these leukemic cells, structural changes, mostly end‐to‐end fusions of chromosomes, appeared (10/12). In contrast, leukemic cells overexpressing Myc with reduced or no Suv39h1 expression had a normal karyotype in primary, secondary, and tertiary transplantations (16/16). Myc‐transduced Suv39h1‐deficient cells showed less critically short telomeres (P < 0.05) compared with Myc‐transduced wild‐type bone marrow cells. Gene expression analysis showed upregulation of genes involved in the alternative lengthening of telomeres (ALT) mechanism. Thus, we hypothesize that loss of Suv39h1 implies activation of the ALT mechanism, in turn ensuring telomere length and stability. Our data show for the first time that Suv39h1 deficiency may prevent chromosomal instability by more efficient telomere stabilization in hematopoietic bone marrow cells overexpressing Myc. © 2013 Wiley Periodicals, Inc.