Current status of prognostic immunohistochemical markers for urothelial bladder cancer.

The management and prognostication of patients with urothelial carcinomas (UCs), the most common histological type of bladder cancer, is mainly based on clinicopathological parameters. Several markers have been proposed to monitor this disease, including individual cell cycle-related proteins such as p53, pRb, p16, p21 and p27. Other putative markers are the oncogene products of FGFR3 and the ErbB family, proliferation markers including Ki-67, Aurora-A and survivin and different components within the immune system. In this review, a total of 12 parameters were evaluated and their discriminatory power compared. It is concluded that, in single-marker analyses, the proliferation markers Ki-67, survivin and Aurora-A offer the best potential to predict disease progression since they were all able to demonstrate independent prognostic power in repeated studies. Markers related to the immune system (e.g. CD8+ cells, regulatory T cells and cyclooxygenase-2 expression) or oncogene products of the ErbB family and FGFR3 are less powerful predictors of outcome or have not been equally well studied. The cell cycle-related proteins p53, pRb, p16, p21 and p27 have been extensively studied, but their usefulness as single prognostic markers remains unclear. However, in multimarker analyses, these markers appear to add prognostic information, indicating that they may contribute to more accurate treatment of UC.

Mechanism of anti-stress activity of Ocimum sanctum Linn, eugenol and Tinospora malabarica in experimental animals.

Effects of restraint stress (RS) and its modulation by O. sanctum (Os), eugenol and T. malabarica (Tm) were evaluated on some biochemical and biophysical parameters in rats. RS induced elevations in blood glucose and urea levels, were unaffected by either Os, eugenol or Tm pretreatment. However, both Os and eugenol lowered RS-induced cholesterol levels. RS also caused a generalized increase in enzyme activity and Os, eugenol or Tm effectively lowered the RS-induced elevations in lactate dehydrogenase (LDH) and alkaline phosphatase. RS also induced (a) increased membrane protein clusterization, (b) increased membrane fluidity and (c) reduced membrane thickness--in RBC membrane, whereas, the effects on the synaptosomal membrane were less marked. The RS-induced changes in RBC membrane dynamics were attenuated/reversed by Os, eugenol or Tm, in a differential manner. These biochemical and membrane changes during Rs and their modulation by the adaptogens are discussed in light of the possible mechanisms of action of these agents, during such aversive stimuli.

Changes in synaptosomal membranes from cerebral cortex due to psychogenic stress in rats.

The changes in synaptosomal membranes in comparison with those of macrophages and mitochondria during repeated psychogenic stress were evaluated using a specially designed multiprobe procedure. Activity of Na,K-ATPase activity was measured as a functional marker for synaptosomal membranes. The interaction of peritoneal macrophages with nitrobluetetrazole (NBT-test) was also evaluated. Some bioenergetic parameters were measured in mitochondria using spectrophotometric techniques. The data revealed profound structural and functional changes in synaptosomal membranes on 15th day of stress. Those in macrophage membranes, present on 3rd and 6th day were not accompanied by functional ones. In conclusion the present data suggest that stress repeated for 15 days leads to a modelled psychopathology in rats and induce selective structural and functional changes in synaptosomal membranes from the cerebral cortex. This model may be used for investigations of the effects of psychotropic drugs.

Effect of some benzamide derivatives on stress-induced behavior and striatum dopamine receptors.

The effects of a new benzamide derivative LIS-630 and the well-known neuroleptic, tiapride, were studied on stress-induced hyper- and hypoactive emotional behavioral reaction of animals depending on the individual ability for perceptive-cognitive activity in stress situations, and their affinity to striatal DA receptors. A modified variant of forced swimming method was used. The affinity of the substances to striatal DA receptors was studied by the radioligand binding method using 3H-spiroperidol. The results show that the psychopharmacological profile of LIS-630 differs significantly from the neuroleptic, tiapride. LIS-630 restored escape behavior from stress situation after preliminary exposure of rats to forced swimming and did not disturb escape behavior in animals more resistant to emotional hypoactivity. LIS-630 reduced immobility time at forced swimming. However, it is not effective in preventing hyperemotional reactions induced by L-dopa and stress. The radioligand binding study shows that LIS-630 did not displace 3H-spiroperidol from the binding sites of striatum membranes. The parameters of displacement with tiapride were satisfactory.

Effect of the N-terminal tetrapeptide of substance P SP (1-4) and tuftsin on the pre- and postsynaptic transmitter outflow in rat adrenal gland slices.

Two structurally related tetrapeptides, the N-terminal tetrapeptide of substance P SP(1-4) and tuftsin, exerted some similarities in modifying immune reactions and normalizing stress-induced disorders in the catecholamine system of adrenals. This paper presents results about the effects of tuftsin and SP(1-4) on the cholinergic-adrenergic interaction in rat adrenal gland slices. Both, tuftsin and SP(1-4) inhibited the nicotine-evoked [3H]noradrenaline outflow (postsynaptic effect), but the effect of SP(1-4) was more pronounced. SP(1-4) also inhibited the electrically stimulated [3H]ACh outflow (presynaptic effect), whereas tuftsin did not affect the ACh outflow. It is suggested that the regulation of the cholinergic-adrenergic interaction in adrenals is mediated by specific receptors, which are different on the pre- and postsynaptic side.

Pharmaco-ethological analysis of antidepressant drug effects.

An ethological approach to the analysis of antidepressant drug action focuses on the restorative effects of these drugs on intraspecies behavior and locomotor activity. The present analysis reveals that iprazid and amphetamine differentially alter locomotion and intraspecies behavior in mice that were pretreated with reserpine. Fluoxetine restores intraspecies behavior, specifically by increasing the number of passive contacts, but without activating locomotion. Trazodon, pyrazidol and clomipramine restore aggression by dominant mice that was suppressed by aversive stimulation. The restoration of intraspecies behavior among laboratory rodents subjected either to reserpine treatment or to prolonged aversive stimulation may reveal the antidepressant effects of drugs.

"Endogenous ligands" of benzodiazepine receptors, their structural analogs. Development of new psychotropic drugs.

This paper presents a review of literature data and results from investigations designed to determine the relation between structure, affinity to benzodiazepine receptors and pharmacological activity of possible endogenous ligands of benzodiazepine receptors and their electronic structural analogs. Structural variations of endogenous ligands of benzodiazepine receptors are substantiated to manifest themselves as active psychotropic drugs. On the basis of these considerations and experimental data, compounds with psychotropic activity and electronic structure, resembling that of "endogenous ligands" of benzodiazepine receptors, were developed.

Behavioural and neurochemical studies of the action of atypical antidepressants.

With a view to finding suitable methods for studying the antidepressive properties of the so-called atypical antidepressants we investigated the relationship between the affinity of these substances for the membrane lipids and their influence on the in vitro accumulation of neurotransmitters, on the radioligand binding and on some behavioural phenomena. The antidepressants tested were found to be localized in the region of the polar head group of the lipid membrane bilayer which serves as a recognition site for various ligands. Unlike the tricyclic antidepressants which inhibit the NA, DA and 5-HT uptake, the atypical antidepressants studied (azaphen, befuraline, pirlindol, inkazan) were less active and inhibited the uptake of only one or two monoamines. A highly significant correlation was also found between the influence of the drugs on the surface electric charge of the lipid membrane bilayer and the inhibition they produced of the neurotransmitter uptake. It was established that the atypical antidepressants studied were less active than the tricyclic antidepressants with respect to the displacement of labelled imipramine from the binding site, suggesting that this test is not very suitable for studying these drugs. With Porsolt's model of behavioural depression in mice all substances tested (tricyclic and atypical antidepressants) exhibited such an action (prevention of the behavioural depression). With the model of depression through escaping the learned helplessness (Anisman's test) in mice under acute conditions the antidepressants studied did not prevent the development of this state while in case of chronic treatment they prevented it.

Systems of reinforcement and drug dependence.

Experimental data are presented in support of the hypothesis on the role of positive and negative reinforcing systems in the mechanism of drug dependence. Drugs with abuse potential (DAP) may change the manner of response to negative emotional stimuli, activate positive emotional reactions in animals, and possess primary reinforcing properties. Reward and punishment systems respond sensitively to withdrawal from DAP or antagonist administration. Catecholaminergic and peptidergic processes are of importance in the mechanisms of the emotionally positive action of DAP.