Low rate of intracerebral hemorrhage after cardiac catheterization in patients with acute ischemic stroke in a large case series.

BACKGROUND AND AIMS: Myocardial infarction complicating acute ischemic stroke (IS) is associated with high mortality, but evidence guiding the acute management is scarce. In particular, data on the risk of intracerebral hemorrhage (ICH) due to early cardiac catheterization including the peri-procedural application of antithrombotic drugs in patients with acute ischemic stroke are limited. Here, we aimed to evaluate the incidence and patient characteristics of ICH after cardiac catheterization in acute stroke patients to help to govern the risk of intracranial bleeding versus the benefits of myocardial reperfusion via cardiac catheterization. METHODS: We screened a consecutive cohort of n = 126 patients with acute ischemic stroke (IS) who underwent cardiac catheterization during the same hospital stay at a large German neurovascular center (LMU Munich). Eventually, we identified n = 42 patients with cardiac catheterization after acute stroke. N = 22/42 patients did not receive neuroimaging post cardiac catheterization and were discharged without any new neurological deficits, n = 20/42 had neuroimaging after cardiac catheterization and were included for final analysis. RESULTS: Cardiac catheterization was performed within a median of 3,6 days after ischemic stroke (No-ICH 7,3 days (IQR, 3,8-16,2) vs. ICH 1,1 days (IQR, 0,8-74,6), p = 0,40), One patient showed new neurological deficits after cardiac procedures (n = 1/42, 2,4 %). New or progressive ICH was ultimately found in 15 % (3/20) of cases. They were classified as HT1, PH1 and PH2 according to ECASS II criteria, respectively. With regards to the coronary catheterization, 85 % of all patients undergoing catheterization ultimately received percutaneous cardiac intervention. ICH was not significantly associated with any of the independent variables. Intrahospital death due to either ischemic stroke, ICH or cardiovascular events did not occur. CONCLUSION: The incidence of ICH in ischemic stroke followed by early cardiac catheterization and application of antithrombotic drugs was comparable to studies reporting on the incidence of ICH in ischemic stroke patients without catheterization. This study's results strengthen the hypothesis that in presence of both, acute myocardial infarction and acute ischemic stroke, the general risk for ICH is not prohibitive of cardiac catheterization.

Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia.

In acute myeloid leukemia (AML), several signaling pathways such as the phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway are deregulated and constitutively activated as a consequence of genetic and cytogenetic abnormalities. We tested the effectiveness of PI3K/AKT/mTOR-targeting therapies and tried to identify alterations that associate with treatment sensitivity. By analyzing primary samples and cell lines, we observed a wide range of cytotoxic activity for inhibition of AKT (MK-2206), mTORC1 (rapamycin) and PI3K/mTORC1/2 (BEZ-235) with a high sensitivity of cells carrying an MLL rearrangement. In vivo PI3K/mTOR inhibition delayed tumor progression, reduced tumor load and prolonged survival in an MLL-AF9(+)/FLT3-ITD(+) xenograft mouse model. By performing targeted amplicon sequencing in 38 MLL-AF9(+) and 125 cytogenetically normal AML patient samples, we found a high additional mutation rate for genes involved in growth factor signaling in 79% of all MLL-AF9(+) samples, which could lead to a possible benefit of this cohort. PI3K/mTOR inhibition for 24 h led to the cross-activation of the ERK pathway. Further in vitro studies combining PI3K/mTOR and ERK pathway inhibition revealed highly synergistic effects in apoptosis assays. Our data implicate a possible therapeutic benefit of PI3K/mTOR inhibition in the MLL-mutated subgroup. Inhibiting rescue pathways could improve the therapeutic efficacy of PI3K-targeted therapies in AML.

Haemocyanins in spiders, III. Chemical and physical properties of the proteins in Dugesiella and Cupiennius blood.

The haemolymph of the tarantulas, Dugesiella (Eurypelma) californica and Dugesiella (Eurypelma) helluo contains high molecular weight haemocyanin (80-82% of total blood proteins) and a second protein not related to haemocyanin (18-20%). In the Lycosid spider, Cupiennius salei, haemocyanin (75% of total blood protein) occurs in two states of association. The haemocyanins were isolated by ultracentrifugation, gel filtration, isoelectric focusing, or preparative gel electrophoresis. Their sedimentation constants are 36.7 S (both tarantulas), 23.4 S and 15.9 S (Cupiennius). After alkaline dissociation, polypeptides sedimenting at 5.8 S (D. californica) and 4.7 S (Cupiennius) were obtained. The molecular weight of the intact functional subunit is (by sedimentation equilibrium) 70 300 (D. californica) and 69 900 (Cupiennius). Copper analysis results in closely similar values. By sodium dodecylsulphate gel electrophoresis, molecular weights of 71 000 (D. californica), 72 000 (Cupiennius) and 74 000 (D. helluo) were obtained. Denaturation with various agents did not lead to smaller polypeptides. The amino acid composition of the haemocyanins was determined (Table 1). The amino end group is blocked. The haemocyanins contain 1.2-1.5% of neutral carbohydrates and 0.3-0.5% of glucosamine (possibly acetylated). The neutral carbohydrates were identified with glucose, mannose, fucose, and arabinose, glucose being the dominant species. Neuraminic acid was not detected. The haemocyanins of the three species cannot be distinguished by their carbohydrate moieties, while there is a significant difference in amino acid composition between tarantula and Cupiennius haemocyanins. The second, non-respiratory protein isolated from spider blood sediments with 16.1 S (Dugesiella) or 15.9 S (Cupiennius). Its isoelectric point is at pH 5.5 It is stable in weakly alkaline solutions but can be denatured to yield polypeptide chains with molecular weights of 95 000 and 110 000. The amino acid composition is reported. As in the haemocyanins, the N-terminus is blocked. The carbohydrate content is 0.9%, glucose being the only sugar identified.