Gene Polymorphisms for PAI-1 Are Associated with the Angiographic Extent of Coronary Artery Disease

Localized regulation of fibrinolytic protein gene expression is associated with the histologic extent of atherosclerosis. This regulation may be dependent on the presence of certain fibrinolytic protein gene polymorphisms. The relationship between the plasminogen activator inhibitor (PAI)-1 HindIII and the tissue plasminogen activator (t-PA) EcoR1 gene polymorphisms and the extent of coronary artery disease (CAD) were investigated in 49 Caucasian patients with symptomatic CAD. There was a strong association between PAI-1, but not t-PA, gene polymorphisms and the extent of CAD detected by coronary angiography. Patients homozygous for the presence or absence of the PAI-1 HindIII (1/1, 2/2 PAI-1) gene polymorphisms had a significantly greater extent of CAD (number of diseased vessels) than patients with the respective heterozygous forms (vs. 1/2 PAI-1, P = 0.05). Stepwise ordinal multiple regression analysis of classic CAD risk factors and fibrinolytic protein genotypes indicated that only the PAI-1 genotypes were predictive of the extent of angiographic CAD (P = 0.019). Analysis of variance between classic risk factors and fibrinolytic protein genotypes identified an association between t-PA genotypes and a history of prior infarction or stroke. Fibrinolytic gene polymorphisms for PAI-1 are associated with the extent of CAD in symptomatic patients and with certain risk factors for coronary atherosclerosis.     

Assessment of motor imagery in cerebral palsy via mental chronometry: The case of walking

Recent studies show varying results on whether motor imagery capacity is compromised in individuals with cerebral palsy (CP). Motor imagery studies in children predominantly used the implicit hand laterality task. In this task participants judge the laterality of displayed hand stimuli. A more explicit way of studying motor imagery is mental chronometry. This paradigm is based on the comparison between the movement durations of actually performing a task and imagining the same task. The current study explored motor imagery capacity in CP by means of mental chronometry of a whole body task. Movement durations of 20 individuals with CP (mean age = 13 years, SD = 3.6) were recorded in two conditions: actual walking and imagined walking. Six unique trajectories were used that varied in difficulty via manipulation of walking distance and path width. We found no main effect of condition (actual walking versus imagining) on movement durations. Difficulty of the walking trajectory did affect movement durations. In general, this was expressed by an increase in movement durations with increasing difficulty of the task. No interaction between task difficulty and movement condition was found. Our results show that task difficulty has similar effects on movement durations for both actual walking and imagined walking. These results exemplify that the tested individuals were able to use motor imagery in an explicit task involving walking. Previous studies using the implicit hand laterality task showed varying results on motor imagery capacity in CP. We therefore conclude that motor imagery capacity is task dependent and that an explicit paradigm as the one used in this study may reveal the true motor imagery capacity. The implications of these findings for the use of motor imagery training are discussed.     

Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience

Acute megakaryocytic leukemia (AMegL) is a rare subtype of acute myeloid leukemia (AML) evolving from primitive megakaryoblasts. Because of its rarity and the lack of precise diagnostic criteria in the past, few series of adults treated with contemporary therapy have been reported. Twenty among 1649 (1.2%) patients with newly diagnosed AML entered on Eastern Cooperative Oncology Group (ECOG) trials between 1984 and 1997 were found to have AMegL. The median age was 42.5 years (range 18-70). Marrow fibrosis, usually extensive, was present in the bone marrow. Of the 8 patients who had cytogenetic studies performed, abnormalities of chromosome 3 were the most frequent. The most consistent immunophenotypic finding was absence of myeloperoxidase in blast cells from 5 patients. In the most typical 3 cases, the leukemic cells were positive for one to 2 platelet-specific antigens in addition to lacking myeloperoxidase or an antigen consistent with a lymphoid leukemia. Myeloid antigens other than myeloperoxidase and selected T-cell antigens (CD7 and/or CD2) were frequently expressed. Induction therapy included an anthracycline and cytarabine in all cases. Complete remission (CR) was achieved in 10 of 20 patients (50%). Two patients remain alive, one in CR at 160+ months. Resistant disease was the cause of induction failure in all but 3 patients. The median CR duration was 10.6 months (range 1-160+ months). The median survival for all patients was 10.4 months (range 1-160+ months). Although half of the patients achieved CR, the long-term outcome is extremely poor, primarily attributable to resistant disease. New therapeutic strategies are needed.     

Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells

PEP005 (ingenol-3-angelate) is a novel anticancer agent extracted from Euphorbia peplus that was previously shown to modulate protein kinase C (PKC), resulting in antiproliferative and proapoptotic effects in several human cancer cell lines. In Colo205 colon cancer cells, exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis. In Colo205 cells exposed to PEP005, a variety of signaling pathways were activated as shown by increased phosphorylation of PKCdelta, Raf1, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK), c-Jun NH(2)-terminal kinase, p38 MAPK, and PTEN. PEP005-induced activation of PKCdelta was associated with its translocation from the cytosol to the nucleus and other cellular membranes. Interestingly, PEP005 treatment also resulted in reduced expression of PKCalpha and reduced levels of phosphorylated active form of AKT/protein kinase B. These data suggest that PEP005-induced activation of PKCdelta and reduced expression of PKCalpha resulted in apoptosis by mechanisms mediated by activation of Ras/Raf/MAPK and inhibition of the phosphatidylinositol 3-kinase/AKT signaling pathways. This study supports ongoing efforts targeting PKC isoforms in cancer therapy with PEP005 alone and in combination with other cytotoxic agents.     

Modulation of associated ovarian carcinoma antigens by 5 cytokines used as single agents or in combination

Optimization of intraperitoneal radioimmunotherapy of ovarian cancer depends on increasing the antigenic expression of tumor cells. For this purpose, we studied the effect of 5 cytokines (IFN-α, IFN-β, IFN-γ, TNF-α and TGF-β), used as single agents or in combination, on 4 ovarian cancer cell lines which present different antigenic profiles with the monoclonal antibodies (MAbs) tested (OC125, OVTL-3, MOv 18 and MOv 19). Analyses were performed by flow cytometry and the Scatchard technique in order to study antigenic modulation. The effect on proliferation was determined by cell counting. Expression of O3 antigen, recognized by the OVTL3 MAb, was increased up to 2.5 times after IFNs and TNF-α (used as single agent) on the 2 lines presenting low basal expression (SHIN-3 and IGROVI). The expression of CAI25 antigen and the antigens recognized by MOv 18 and MOv 19 MAbs was not increased by any of the cytokines tested. The combination IFN-γ + TNF-α was synergistic on cytotoxicity and enhanced O3 expression, providing 10 times as many sites per cell on the SHIN-3 line. For 3 other associations (IFN-α + IFN-γ, IFN-β + IFN-γ and IFN-α + TNF-α), there was an additive effect on O3 expression and on cell cytotoxicity. © 1994 Wiley-Liss, Inc.     

Local carotid atherosclerotic plaque proteins for the identification of circulating biomarkers in coronary patients

Objective

To identify circulating biomarkers that originate from atherosclerotic vulnerable plaques and that could predict future cardiovascular events.

Methods

After a protein enrichment step (combinatorial peptide ligand library approach), we performed a two-dimensional electrophoresis comparative analysis on human carotid plaque protein extracts (fibrotic and hemorrhagic atherosclerotic plaques). In silico analysis of the biological processes was applied on proteomic data. Luminex xMAP assays were used to quantify inflammatory components in carotid plaques. The systemic quantification of proteins originating from vulnerable plaques in blood samples from patients with stable and unstable coronary disease was evaluated.

Results

A total of 118 proteins are differentially expressed in fibrotic and hemorrhagic plaques, and allowed the identification of three biological processes related to atherosclerosis (platelet degranulation, vascular autophagy and negative regulation of fibrinolysis). The multiplex assays revealed an increasing expression of VEGF, IL-6, IL-8, IP-10 and RANTES in hemorrhagic as compared to fibrotic plaques (p < 0.05). Measurement of protein expressions in plasmas from patients with stable and unstable coronary disease identified a combination of biomarkers, including proteins of the smooth muscle cell integrity (Calponin-1), oxidative stress (DJ-1) and inflammation (IL-8), that allows the accurate classification of patients at risk (p = 0.0006).

Conclusion

Using tissue protein enrichment technology, we validated proteins that are differentially expressed in hemorrhagic plaques as potential circulating biomarkers of coronary patients. Combinations of such circulating biomarkers could be used to stratify coronary patients.     

Prophylactic protective ventilation: lower tidal volumes for all critically ill patients?

High tidal volumes have historically been recommended for mechanically ventilated patients during general anesthesia. High tidal volumes have been shown to increase morbidity and mortality in patients suffering from acute respiratory distress syndrome (ARDS). Barriers exist in implementing a tidal volume reduction strategy related to the inherent difficulty in changing one's practice patterns, to the current need to individualize low tidal volume settings only for a specific subgroup of mechanically ventilated patients (i.e., ARDS patients), the difficulty in determining the predicated body weight (requiring the patient's height and a complex formula). Consequently, a protective ventilation strategy is often under-utilized as a therapeutic option, even in ARDS. Recent data supports the generalization of this strategy prophylactically to almost all mechanically ventilated patients beginning immediately following intubation. Using tools to rapidly and reliably determine the predicted body weight (PBW), as well as the use of automated modes of ventilation are some of the potential solutions to facilitate the practice of protective ventilation and to finally ventilate our patients?? lungs in a more gentle fashion to help prevent ARDS.     

Combined Transradial and Transpedal Approach for Femoral Artery Interventions

Objectives

The purpose of this prospective study was to evaluate the acute success and complication rates of combined transradial and transpedal access for femoral artery intervention.

Ultrasound-guided central venous cannulation is superior to quick-look ultrasound and landmark methods among inexperienced operators: a prospective randomized study

Objective

Quick-look ultrasound with a skin mark (UM) has been frequently used for central vein cannulation. The aim of this study is to compare this method with landmark (LM) and ultrasound-guided (UG) cannulation of jugular and femoral veins by inexperienced operators.

Design

Prospective randomized single-center study.

Setting

A medical intensive care unit (ICU) of a university medical center.

Patients

Patients requiring jugular or femoral central cannula placement.

Intervention

Each inexperienced resident randomly inserted a central venous line using the UM, LM or UG technique.

Measurements and findings

The primary outcome was the success rate, and secondary outcomes were the placement time, number of attempts, mechanical complication rate, and catheter colonization rate. A total of 118 patients were randomly assigned to the three groups. The mean age of patients included in the study was 65 ± 15 years, and the mean Simplified Acute Physiology Score 2 (SAPS2) was 57 ± 20. The success rate was higher in the UG group than in the LM and UM groups (100, 74, and 73 %, respectively; p = 0.01). The total number of mechanical complications was higher in the LM and UM groups than in the UG group (24 and 36 versus 0 %, respectively; p = 0.01). The number of attempts and the access time were higher in the LM group than in the UG group, but not compared with the UM group. No difference in terms of catheter colonization was observed between the three groups.

Conclusions

Ultrasound-guided cannulation of the internal jugular or femoral vein by inexperienced residents appears to be more reliable than the LM or UM methods and was associated with a lower mechanical complication rate among ICU patients.