We have recently reported that ligation of the CD44 cell surface antigen with A3D8 monoclonal antibody (mAb) triggers incomplete differentiation and apoptosis of the acute promyelocytic leukemia (APL)-derived NB4 cells. The present study characterizes the mechanisms underlying the apoptotic effect of A3D8 in NB4 cells. We show that A3D8 induces activation of both initiator caspase-8 and -9 and effector caspase-3 and -7 but only inhibition of caspase-3/7 and caspase-8 reduces A3D8-induced apoptosis. Moreover, A3D8 induces mitochondrial alterations (decrease in mitochondrial membrane potential DeltaPsi m and cytochrome c release), which are reduced by caspase-8 inhibitor, suggesting that caspase-8 is primarily involved in A3D8-induced apoptosis of NB4 cells. However, the apoptotic process is independent of TNF-family death receptor signalling. Interestingly, the general serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) decreases A3D8-induced apoptosis and when combined with general caspase inhibitor displays an additive effect resulting in complete prevention of apoptosis. These results suggest that both caspase-dependent and serine protease-dependent pathways contribute to A3D8-induced apoptosis. Finally, A3D8 induces apoptosis in all-trans-retinoic acid-resistant NB4-derived cells and in APL primary blasts, characterizing the A3D8 anti-CD44 mAb as a novel class of apoptosis-inducing agent in APL. 相似文献
Neuropsychiatric disturbances are extremely common in Alzheimer’s disease (AD), and represent integral features of the illness,
as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence
of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved
to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent
on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle
formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally
in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these
studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or
some other mechanism, is a useful therapeutic agent to modify disease progression in AD. 相似文献
Background: Tight perioperative control of blood glucose improves the outcome of diabetic patients undergoing cardiac surgery. Because stress response and cardiopulmonary bypass can induce profound hyperglycemia, intraoperative glycemic control may become difficult. The authors undertook a prospective cohort study to determine whether poor intraoperative glycemic control is associated with increased intrahospital morbidity.
Methods: Two hundred consecutive diabetic patients undergoing on-pump heart surgery were enrolled. A standard insulin protocol based on subcutaneous intermediary insulin was given the morning of the surgery. Intravenous insulin therapy was initiated intraoperatively from blood glucose concentrations of 180 mg/dl or greater and titrated according to a predefined protocol. Poor intraoperative glycemic control was defined as four consecutive blood glucose concentrations greater than 200 mg/dl without any decrease in despite insulin therapy. Postoperative blood glucose concentrations were maintained below 140 mg/dl by using aggressive insulin therapy. The main endpoints were severe cardiovascular, respiratory, infectious, neurologic, and renal in-hospital morbidity.
Results: Insulin therapy was required intraoperatively in 36% of patients, and poor intraoperative glycemic control was observed in 18% of patients. Poor intraoperative glycemic control was significantly more frequent in patients with severe postoperative morbidity (37% vs. 10%; P < 0.001). The adjusted odds ratio for severe postoperative morbidity among patients with a poor intraoperative glycemic control as compared with patients without was 7.2 (95% confidence interval, 2.7-19.0). 相似文献
Blood velocity is a functional parameter that is not easily assessed noninvasively, especially in small animals. A new noninvasive method that uses magnetic resonance angiography (MRA) to measure blood flows is proposed. This method is based on the time-of-flight (TOF) phenomenon. By initially suppressing the signal from the stationary spins in the area of interest, it is possible to sequentially visualize only the signal from the moving spins entering a given volume. With this method, 3D cine images of the blood flow can be generated by positive contrast, with unparalleled spatial (<200 microm) and temporal resolutions (<10 ms/image). As a result, it is possible to measure flow in sinuous paths. The present method was applied in vivo to measure the blood velocity in mouse carotid arteries. Because of its robustness and simplicity of implementation, this method has numerous potential applications for fundamental studies in small animal models. 相似文献
A behavioral method for measuring the electrical sensitivity of directly stimulated elements in the brain is described and applied to the medial forebrain bundle (MFB) reward path and the tectospinal circling path. Equations are derived from which threshold current densities may be calculated from knowledge of the electrode tip dimensions and the current required to produce criterion behavior, which is a function of electrode size. Four different sizes of electrode were implanted in the MFB of rats and self-stimulation rates plotted against stimulating current. The mean currents for criterion bar-pressing rates of 25% and 55% of maximum rate were determined for each electrode size and the values used to calculate average threshold current densities. Two sizes of electrode were implanted in the tectospinal tract of rats and the average currents to produce circling at 0.2 and 0.4 turns/s were measured. The threshold current densities for self-stimulation axons were about 5 times as large as those for circling, in accordance with other evidence that tectal circling path axons are larger than those of the MFB reward path. 相似文献