Endogenous brain angiotensin II disrupts passive avoidance behavior in rats

The presence of angiotensinogen, the precursor of angiotensin II (ANG II), in brain tissue and in cerebrospinal fluid (CSF) allows stimulation of endogenous brain ANG II by renin. Passive avoidance tests were performed in female Wistar rats. The animals received an electrical shock after entering a black box on the first experimental day. Avoidance was tested every 24 h for 5 consecutive days. Renin in doses of 0.01 and 0.1 units was injected once into the lateral brain ventricles 2 min before the first test. CSF ANG II increased from 40 to 4547 and 5152 fmol per ml (means), respectively. A dose-dependent disruption of avoidance learning was observed, the frequency to enter the black box increasing from 11% (control) to 29% and 46%, and the latency decreasing from 165 (control) to 143 and 116 sec, respectively. These effects were statistically significant (P less than 0.001) for more than 24 h and returned to control levels after 48 to 120 h. Administration of the converting-enzyme inhibitor SQ 14225 i.v.t. prior to renin injections abolished the renin effects. Injections of renin given 22 h after learning were without effect.     

Proximal and Distal Predictors of AIDS Risk Behaviors among Inner-city African American and European American Women

AIDS risk behavior and attitudes towards safer sex were studied in a sample of 666 African American and 626 European American women. Condom use, AIDS-related knowledge, risk perception, self-efficacy beliefs, attitudes and perceived partner attitudes, and an assertive coping style were analyzed with regard to mean differences and predictive power in both ethnic groups. Compared to European American women, African American women had less knowledge and lower self-efficacy beliefs towards safer sex behavior, but they perceived themselves to be at more risk and reported greater condom use. Further, ethnicity was found to moderate the effects of the psychological predictors on safer sex behavior. This moderator effect was tested using a structural equation modeling design. In both groups, risk perception was the strongest predictor of condom use. Among African American women, social-cognitive barriers (e.g. low self-efficacy beliefs, negative attitude towards condom use) worked as a second predictor and mediator of the effects of risk perception on condom use. In contrast, among European American women, social-cognitive factors had no effect on condom use. In general, prediction of safer sex behavior was stronger among African American women.     

Developing an expert system for immunophenotypical diagnosis in immunodeficiency. Age-related reference values of peripheral blood lymphocyte subpopulations in Hungary

In the process of developing a decision support system based on flow cytometric data for the diagnosis of immunodeficiency, assessment of lymphocyte subpopulations in human peripheral blood provides the key for further analysis. Samples from 273 'healthy' Hungarian subjects were measured between 1998 and 1999. Immunophenotypic data are compared here (unadjusted for gender) by different age groups: I 0-6 years (n=45); II 7-18 years (n=71); III 19-35 years (n=72); IV 36-55 years (n=48); and V 56-99 years (n=37). Two-color flow cytometric analysis was performed using the Becton Dickinson Simultest IMK Plus kit (CD45/CD14, isotype control, CD3/CD19, CD4/CD8, CD3/HLA-DR, CD3/CD16+56). All lymphocyte subpopulations were measured in all blood samples identically. The quality criteria involved at least 95% of total lymphocytes in the analysis gate, homogenous CD45+ lymphocyte population (minimum of 2000 events in the gate, CD45+ >95%). The frequency of B lymphocytes was the highest, significantly, in the youngest Hungarian subjects, but there were no significant changes with age comparing the data of other II-V age groups. On the other hand, some T subpopulations changed with aging; both CD4 and CD8 subsets varied over time including the elevation of the fraction of activated T cells as well as LGL-NK cells. Some of these changes were significant by statistical tests. Interpretation of flow cytometric data is time-consuming and requires human knowledge of an expert laboratory staff. To facilitate the diagnosis of immunodeficiency, a pilot study aiming at the development of a diagnostic algorithm has been initiated. Algorithm nodes compare the frequency of each lymphocyte subpopulations to the generated reference values. This knowledge-based system describes a short summary report as a result of the comparison, and points to some values requiring further human examination to reach a final conclusion. These reference values and the expert system appear to be a recommended basis for comparing and combining results from different laboratories.     

Theory of mind and motion perception in schizophrenia

This study investigated the relationship between theory of mind (ToM) deficits and visual perception in patients with schizophrenia (N=52; 17 remitted and unmedicated) compared with healthy controls (N=30). ToM was assessed with the Eyes Test, which asked participants to choose which of 4 words best described the mental state of a person whose eyes were depicted in a photograph. Visual perception was evaluated with form and motion coherence threshold measurements. Results revealed that patients with schizophrenia (both remitted and nonremitted) showed deficits on the Eyes Test and the motion coherence task. ToM dysfunctions were associated with higher motion coherence thresholds and more severe negative symptoms. This suggests that ToM deficits are related to motion perception dysfunctions, which indicates a possible role of motion-sensitive areas in the pathophysiology of schizophrenia.     

Blocking lymphotoxin-beta receptor activation diminishes inflammation via reduced mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression and leucocyte margination in chronic DSS-induced colitis

The lymphotoxin-beta receptor (LTbetaR) pathway is critical for maintenance of organized lymphoid structures and is involved in the development of colitis. To investigate the mechanisms by which LTbetaR activation contributes to the pathology of chronic inflammation we used a soluble LTbetaR-Ig fusion protein as a competitive inhibitor of LTbetaR activation in the mouse model of chronic colitis induced by oral administration of dextran sulphate sodium. Strong expression of LTbeta which constitutes part of the LTalpha(1)beta(2) ligand complex was detected in colonic tissue of mice with chronic colitis. Treatment with LTbetaR-Ig significantly attenuated the development and histological manifestations of the chronic inflammation and reduced the production of inflammatory cytokines such as TNF, IL-1beta, and IL-6. Moreover, LTbetaR-Ig treatment significantly down-regulated mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression, leading to reduced leucocyte rolling and sticking in postcapillary and collecting venules and reduced extravasation into the intestinal mucosa as quantified by in vivo fluorescence microscopy. Thus, LTbetaR pathway inhibition ameliorates DSS-induced experimental chronic colitis in mice by MAdCAM-1 down-regulation entailing reduced lymphocyte margination and extravasation into the inflamed mucosa. Therefore, a combined treatment with reagents blocking T cell-mediated perpetuation of chronic inflammation such as LTbetaR-Ig together with direct anti-inflammatory reagents such as TNF inhibitors could constitute a promising treatment strategy for chronic colitis.     

Reconstitution of T-cell repertoire after autologous stem cell transplantation: influence of CD34 selection and cytomegalovirus infection.

The period of immunodeficiency following autologous hematopoietic stem cell transplantation is characterized by transient expansions of CD8+CD45RO+CD57+ T lymphocytes, displaying markers of an activated phenotype. Most evidence suggests that this early reconstitution results from proliferation of mature T cells that have survived conditioning or were transferred with the graft. Although homeostatic mechanisms are thought to act in maintaining total T-cell numbers, the degree to which antigen-driven expansions contribute and the nature of the stimulating antigens remain unclear. CD34 selection of stem cell grafts reduces the available T-cell pool, potentially delaying immune reconstitution and resulting in increased infective complications. In the allogeneic transplantation setting, lymphopenia has been associated with cytomegalovirus (CMV) infection risk and, if persistent, with adverse outcome. We prospectively studied patients undergoing CD34-selected (n = 13) or unselected (n = 13) autologous hematopoeitic stem cell transplantation for immune reconstitution and CMV infection. No significant differences were demonstrated between graft types with respect to lymphocyte subset recovery, T-cell receptor beta-chain variable region spectratype diversity, or CMV DNA detection rates (45% versus 40%). CMV infection was associated with a trend toward higher rather than lower CD8+ counts at 6 weeks posttransplantation (P =.08) that became significant by 3 months (P=.007), and that was associated with decreased T-cell receptor beta-chain variable region spectratype diversity (P =.01). CMV-specific HLA-tetramer analysis demonstrated transient expansions with CDR3 lengths corresponding to those of some of the major posttransplantation T-cell expansions demonstrated by spectratype analysis suggesting that CMV-specific T cells contribute to the pattern of immune reconstitution.     

Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat

The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function.Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.     

The repair of DNA damage induced in human peripheral lymphocytes with styrene oxide

Isolated human peripheral lymphocytes were treated in vitro with styrene-7, 8-oxide (SO) and the kinetics of the repair of induced DNA damage was assessed by comet assay during further incubation of lymphocytes. Using a modified assay we measured simultaneously the number of single strand breaks in DNA (SSBs) and the sites sensitive to endonuclease III (endo III) that most probably represent abasic sites in DNA molecules. SO induced DNA damage in a dose-dependent manner and both SSBs and endo III sites were removed from the DNA by a repair process with a half time about 2-4 hours. The damage was repaired completely within 12 hours after the treatment.     

Strain-specific restriction of the antiphagocytic property of group A streptococcal M proteins

Group A streptococcal M proteins are type-specific virulence factors that inhibit phagocytosis. We used two M proteins, M5 and Emm22, to analyze the influence of genetic background on the properties of M proteins. Mutant strains, engineered to lack these M proteins, were complemented with genes encoding the homologous or heterologous M protein, and the complemented strains were analyzed for phagocytosis resistance. Neither the M5 nor the Emm22 protein conferred phagocytosis resistance in the heterologous background, but they did do so in the homologous background. This was not due to lack of surface expression in the heterologous background. Moreover, the M5 and Emm22 proteins expressed in heterologous background appeared to have normal structure, since they were not affected in their ability to bind different human plasma proteins. In particular, M5 or Emm22 had normal ability to bind human complement inhibitors, a property that has been implicated in phagocytosis resistance. Results similar to those obtained with M5 and Emm22 were obtained in experiments with the M6 and Emm4 proteins. Together, these data suggest that the surface expression of M protein alone may not be sufficient to confer phagocytosis resistance and consequently that strain-specific factors other than M and Emm proteins may contribute to the ability of group A streptococci to resist phagocytosis.