The evaluation of the efficacy of hemosorption and plasmapheresis in IHD complicated by chronic heart failure

Hemosorption and plasmapheresis were studied for effects on lipid peroxidation, antioxidant blood activity, platelet hemostasis, microcirculation, myocardial contractility and intracardiac hemodynamics. The results demonstrated that antioxidant blood response is a key criterion responsible for decreased efficacy of hemosorption and plasmapheresis in patients with progressive angina pectoris with chronic heart failure. The results of hemosorption and plasmapheresis in the above patients may become better if an adjuvant antioxidant therapy is used.     

Synthesis and pharmacology of conformationally restricted raloxifene analogues: highly potent selective estrogen receptor modulators

The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator (SERM) which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. In vivo structure-activity relationships and molecular modeling studies have indicated that the orientation of the basic amine-containing side chain of 1, relative to the stilbene plane, is an important discriminating factor for the maintenance of tissue selectivity. We have constructed a series of analogues of 1 in which this side chain is held in an orientation which is orthogonal to the stilbene plane, similar to the low-energy conformation predicted for raloxifene. Herein, we report on the synthesis of these compounds and on their activity in a series of in vitro and in vivo biological assays reflective of the SERM profile. In particular, we describe their ability to (1) bind the estrogen receptor, (2) antagonize estrogen-stimulated proliferation of MCF-7 cells in vitro, (3) stimulate TGF-beta3 gene expression in cell culture, (4) inhibit the uterine effects of ethynyl estradiol in immature rats, and (5) potently reduce serum cholesterol and protect against osteopenia in ovariectomized (OVX) rats without estrogen-like stimulation of uterine tissue. These data demonstrate that one of these compounds, LY357489,4, is among the most potent SERMs described to date with in vivo efficacy on bone and cholesterol metabolism in OVX rats at doses as low as 0.01 mg/kg/d.     

Hemodynamic effect of plasma DNA

To reveal the hemodynamic effect of plasma DNA, the authors measured the concentrations of plasma DNA, the length of its molecular fragments, and hemodynamic resistance/Toms effect. The Toms effect was detected in all blood samples from 10 healthy donors and 39 patients without acute stroke caused by atherosclerosis of the head great arteries with and without arterial hypertension. There was a clear inverse relationships between the plasma concentrations of DNA which had only long-molecular fragments in healthy persons and the hemodynamic resistance of its blood flow samples. The patient blood plasma had significant increased DNA concentrations but their molecular fragments were long and short. Inverse relationships between the plasma DNA concentration and the hemodynamic resistance of the patients' blood flow samples had a less correlation coefficient due to the high proportion of short DNA molecular fragments. The Toms effect was shown in the DNA solution prepared only from human funic blood where the DNA molecular fragments were long. The Toms effect was absent in the solutions prepared from the commercial cattle or salmon sperm DNA which contained shorter DNA molecular fragments. It is concluded that plasma DNA has a hemodynamic effect and the origin of long-molecular fragments of DNA which is typical for healthy young persons and short DNA molecular fragments that additionally appear in patients with vascular disorders is different.     

Studies on supratentorial subdural bleeding using a porcine model

A porcine model for an acute lethal arterial subdural bleeding in man is presented. Blood from the abdominal aorta was led via an electronic drop recorder into a collapsed intracranial subdural rubber balloon. Systemic arterial pressure (SAP), two intracranial pressures and 6 other vital parameters were monitored continuously in spontaneously breathing (n = 4) and mechanically ventilated (n = 4) pigs. In both animal groups bleeding caused an immediate rise in intracranial pressures (ICP) with transtentorial pressure gradients developing. As a result the cerebral perfusion pressures (CPP) decreased progressively, leading to an isoelectric EEG. In spontaneously breathing animals, the pressure changes resulted in apnoea within 2-4 minutes, irregularities in heart rhythm and in a marked rise in SAP (the Cushing reaction). A final collapse of all pressures occurred after 222 +/- 68 sec at a mean bleeding volume of 10.3 +/- 1.9 ml. In contrast, in mechanically ventilated animals, the course of bleeding was less dramatic. No change in cardiac rhythm or rise in SAP appeared despite a larger mean bleeding volume (12.0 +/- 1.6 ml). Instead, SAP slowly fell, reaching a level of approximately 40 mm Hg within 1 hour, while CPP concomitantly decreased from 120 mm Hg to 15 mm Hg. The findings in this and in a parallel study are explained in terms of the intracranial volume tolerance concept (Zwetnow et al. 1986). The beneficial effect of assisted ventilation on the course of subdural bleeding is multifactorial, involving both metabolic and mechanical mechanisms.     

Properties of soluble and membrane intestinal hydrolases in Macaca rhesus monkeys

Evidence from several central nervous system (CNS) inflammatory disease models suggests that intrathecal complement synthesis may contribute to early inflammatory events in the brain. In this study, we examined the expression of the receptor for C5a (C5aR), a potent inflammatory and chemotactic factor, in the brains of transgenic mice with constitutive astrocyte expression of interleukin-3 (IL-3), a hematopoietic and immunomodulatory cytokine. By in situ hybridization, we demonstrated that cells infiltrating the cerebellar meninges, the cerebellum, and demyelinating lesions in the cerebellum were strongly positive for C5aR mRNA. By immunohistochemistry, the infiltrating cells expressing the C5aR were identified as macrophages based on staining with antibodies to the complement receptor type 3 and F4/80, a mouse macrophage-specific marker. In addition, some of the cells in cerebellar lesions were positive for the astrocyte-specific marker, glial fibrillary acidic protein, suggesting that a subpopulation of astrocytes in these lesions express elevated levels of the C5aR. Increased C5aR expression was also observed in cortical neurons in the occipital cortex and in pyramidal neurons in the cornu ammonis and subiculum of the hippocampus, at both the protein and mRNA levels. These data suggest that IL-3 may play an immunomodulatory role in C5aR expression on several cell types in the brain and that increased C5aR expression correlates with the pathology seen in this model. The transgenic mice used in this study provide a useful tool for characterizing the mechanism of regulation of the C5aR expression and for examining the functions of this chemotactic receptor in CNS inflammation.     

Cytotoxicity of murine B lymphocytes induced by human VH4-34 (VH4.21) gene-encoded monoclonal antibodies

We previously found that a ventricular isovolumic pressure-time curve could be well fitted by the difference between two S-shaped logistic curves for the pressure rising and falling components, and called it "hybrid logistic" function: P(t)=A/[1+exp[-(4B/A)(t-C)]]-D/[1+exp[-(4E/D)(t-F)]]+G. We reported that the parameters of this hybrid logistic function are useful to characterize left ventricular contraction and relaxation comprehensively. In this study, we investigated how well this hybrid logistic function could fit the isometric twitch force-time curves of cross-circulated right ventricular papillary muscles of 7 dogs. This function precisely fitted the isometric force curves with correlation coefficients above 0.9996, much better than another fitting function (F(t)=C(t/A)(B)exp[1-(t/A)(B)]) proposed by Nwasokwa. The present results indicate that our hybrid logistic function can also reasonably express the canine right ventricular papillary muscle isometric twitch force-time curve. We suggest the possibility that the parameters of this hybrid logistic function are also useful to comprehensively characterize right ventricular papillary muscle twitch contraction and relaxation.     

The effect of the repeated experience of aggression in daily confrontations on the individual and social behavior of male mice

The influence of repeated experience of aggression in daily intermale confrontations on individual and social behaviour was studied in male mice of C57BL/6J (C57) and CBA/Lac (CBA) strains. Repeated experience of aggression led to a decrease of emotionality in males of highly emotional CBA strain and increase in exploratory activity in the open field and exploratory activity tests, decrease of immobility time in Porsolt's test and pain sensitivity estimated by the "hot plate" test. Low emotional C57 males did not change their individual behaviour in different situations under the influence of repeated experience of aggression. However, aggressive C57 mice demonstrated anxiety-like behaviour estimated in the plus-maze test. In the partition test aggressive mice of both strains showed an increase in communicative level (as a reaction to a familiar male) in comparison with their behaviour before aggressive confrontations. Behavioural reaction to a receptive female under unfamiliar conditions decreased which testified to a decrease in sexual motivation. It is concluded that formation of the aggressive type of social behaviour is accompanied by changes in the individual and social behaviour of male mice. Characteristics of these changes are genetically determined and depend on the duration of confrontations.