Discriminative stimulus properties of β-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors

The discriminative stimulus properties of three -carboline derivatives were studied in three groups of rats trained, respectively, to discriminate diazepam (2.5 mg/kg IP), chlordiazepoxide (CDP, 5 mg/kg IP) or pentylenetetrazol (PTZ, 15 mg/kg IP) from saline in standard procedures employing two-lever operant chambers. Two -carbolines, ZK 91296 and ZK 93423, substituted for the benzodiazepines in both CDP- and diazepam-trained rats. The neutral benzodiazepine antagonist Ro 15-1788 blocked the diazepam discriminative stimulus and the ability of ZK 91296 to substitute for diazepam. A third -carboline, FG 7142, was not identified as benzodiazepine-like in generalization tests in either diazepam- or CDP-trained rats, but when administered together with CDP antagonized the benzodiazepine discriminative stimulus. In rats trained to discriminate PTZ from saline (a discrimination which is thought to depend on the anxiogenic properties of PTZ) the PTZ cue was antagonized by diazepam and ZK 93423, and partially antagonized by ZK 91296. The PTZ cue generalized to FG 7142 and this generalization was partially antagonized by Ro 15-1788. These results suggest that the three -carbolines provide more than one kind of discriminative stimulus, consistent with the classification of ZK 93423 as an agonist at central benzodiazepine receptors, with ZK 91 296 as a partial agonist, and with FG 7142 as an inverse agonist. Pharmacologically, ZK 93 423 and ZK 91 296 may exhibit anxiolytic qualities, whereas FG 7142 produces anxiogenic effects.     

Chronic ethanol consumption impairs receptor-mediated endocytosis of MAA-modified albumin by liver endothelial cells

Alcoholic liver disease has been associated with abnormalities in receptor-mediated endocytosis (RME) which results in abnormal degradation of metabolically altered proteins. Model systems using formaldehyde-modified albumin (f-Alb) have shown an impairment in RME following chronic alcohol consumption utilizing both in situ perfused rat livers and isolated rat liver endothelial cells (LECs). The discovery that alcohol metabolite derived aldehydes can modify proteins prompted a study to determine if malondialdehyde-acetaldehyde-modified albumin (MAA-Alb) would be degraded similar to that reported for f-Alb, and whether ethanol-fed rats would demonstrate an impaired RME with respect to this ligand which occurs as a consequence of chronic ethanol consumption. MAA-Alb was degraded slightly more than f-Alb in both in situ perfused livers and at the single cell level. This degradation was completely inhibited with 100x unlabeled f-Alb, which suggests the use of a similar receptor. Following alcohol consumption there was a 50-60% decrease in MAA-Alb degradation in whole livers and isolated LECs. Utilizing isolated LECs it was determined that impairment in internalization was the most likely mechanism for the decrease in the amount of MAA-Alb that was degraded. These data show that chronic alcohol consumption by rats does in fact impair RME of alcohol metabolite-derived adducted proteins, and this impairment is due to a defect in the post-internalization step rather than the binding or degradation of the modified protein.     

Elective cesarean hysterectomy--revisited

A review of 80 cases of planned or anticipated cesarean hysterectomies done at major centers in the greater Los Angeles area is presented. There were no deaths and five cases of morbidity. Nineteen percent, or one of five cases, required blood transfusions. According to the recommendation of the American Association of Blood Banks, a program of homologous blood replacement should be instituted. Cesarean hysterectomy is a formidable procedure but should not be discarded. In proper hands there are numerous advantages to the operation. Residency training programs should include the teaching of planned or anticipated cesarean hysterectomy in order that skills for the occasional emergency cesarean hysterectomy may be developed.     

Topoisomerase II inhibitors in AML: past,present, and future

ABSTRACT

Introduction: Topoisomerase II inhibitors have long been used in the frontline and as salvage therapy for AML, with daunorubicin and idarubicin being prototypical agents in this therapeutic class, classically in combination with nucleoside analogs, e.g. cytarabine. Most recently, several other compounds from this drug class have or are being investigated.

Areas covered: The current paper reviews older and newer topoisomerase II inhibitors in clinical development for the treatment of AML. The authors discuss the clinical use of these agents, current trials involving them as well as their safety profile. Important side effects of these medications including therapy-related AML (t-AML) are also covered.

Expert opinion: Topoisomerase II inhibitors have helped improve outcomes in AML. Recently, the FDA approved several agents including CPX-351 for the treatment of secondary and t-AML. CPX-351 may have applicability in other high-risk myeloid diseases. Future directions include a combination of these agents with other targeted therapies. Finally, the authors believe that small molecule inhibitors, such as venetoclax and possibly immunotherapy options could also be incorporated to our treatment paradigm in selected patients.     

Epilepsy identification based on EEG signal using RQA method

PurposeEpilepsy is one of the most common neurological diseases and its cause is not unequivocal. Thus, additional methods and searches that may help to diagnose the disease are used in the clinical practice. In this study, we tested the possibility of using the Recurrence Quantification Analysis (RQA) method to identify epilepsy and present the analysis of EEG signals of healthy patients and epileptic patients by the RQA method.Materials/methodsThe recordings of signals belong to 13 patients, which were divided into 2 groups: Group A (5 epileptic patients) and Group B (8 healthy patients). In this study Fp1, Fp2, T3 and T4 electrodes were considered in the analysis using the RQA method.ResultsIt is difficult to explore the dynamics of signals by linear methods. In this study, another way of analyzing the dynamics of signals by the RQA method is presented. The RQA method revealed differences in the dynamics between the epileptic and normal signals, which seemed important in an organoleptic way. It was found that the dynamics of epileptic signals is more periodic than normal signals. To confirm the correctness of the statements issued for the RQA data the Principal Component Analysis mapping was applied. This method showed more clearly the differences in the dynamics of both signals.ConclusionsThe RQA method can be used to identify nonlinear biomedical signals such as EEG signals.