Rationale: Despite decades of research specifying harmful effects produced by 3,4-methylenedioxymethamphetamine (MDMA; a principal component of 'ecstasy' pills), young people (and adults) continue to use it.In an attempt to model human MDMA consumption patterns, preclinical investigators have sought to establish reliable patterns of intravenous MDMA self-administration in rodents. Objective: The objective of this report is to offer a critical review of published data (including our own novel findings) that reveal MDMA self-administration in rodents. Results: The data indicate that MDMA serves as a reinforcer in rodents, though the responses are not similar to those previously reported for psychostimulants (i.e., cocaine). Important differences between rodent models and human use patterns include frequency of dosing and dosage exposure, routes of administration, tolerance that develops to MDMA after repeated exposure, polydrug use in humans but not by rodents, limits on the repertoire of behaviors that can be exhibited by rodents undergoing IV self-administration procedures, and the question of neurotoxicity as it relates to models of self-administration. Conclusions: While MDMA is not as potent a reinforcer as other drugs of abuse, the fact remains that young people and adults continue to use the drug, and therefore, additional research is needed to determine why drugs with low reinforcing effects continue to be abused.

Background: Intranasal inoculation of Streptococcus pneumoniae D39 serotype 2 causes fatal pneumonia in mice. The cytotoxic and inflammatory properties of pneumolysin (PLY) have been implicated in the pathogenesis of pneumococcal pneumonia.

Antibody-based approaches to pneumococcal disease may hold promise for immunocompromised patients in whom vaccines are less immunogenic and/or in the context of antimicrobial resistance. Antibody-mediated protection against experimental pneumococcal pneumonia has been shown to depend on immunoregulation, but the relationship between antibody and protection against pneumococcal sepsis and immunoregulation has not been examined. Similarly, the requirement for B and T cells for antibody efficacy is not known. In this study, we determined the efficacy of the human pneumococcal capsular polysaccharide serotype 3-specific, and SCID mice and investigated its effect on cytokine and chemokine expression in sera and spleens from mice with intact cellular immunity. A7 is known to be protective against systemic infection with serotype 3 and to require complement for efficacy. Compared to that of an isotype control antibody, A7 administration prolonged the survival of mice of each immunodeficient strain and was associated with a significant reduction in CFU in blood, lung, and spleen samples and a significantly reduced level of keratinocyte-derived chemokine (KC), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2) expression in normal and sIgM ؊/؊ mice. Studies with mice treated with penicillin revealed similar reductions in CFU and similar levels of IL-6, KC, or MIP-2 expression in A7-and penicillin-treated mice. These findings demonstrate that natural IgM and B and T cells are dispensable for A7-mediated protection against experimental pneumococcal sepsis and suggest that the efficacy of antibody-mediated protection depends on immunomodulation. Taken together, our data extend the association between antibody-mediated protection and immunomodulation to protection against systemic pneumococcal infection and to a clinically important serotype often responsible for pneumococcal sepsis.

No abstract

Acquired antibody immunity to Streptococcus pneumoniae (pneumococcus) has been linked to serotype (ST)-specific opsonic antibodies to the relevant pneumococcal capsular polysaccharide (PPS) that mediate protection by enhancing the bactericidal effect of host phagocytes. Despite the well-recognized role of opsonic IgG in host defense against pneumococcus, PPS-specific monoclonal antibodies (MAbs) that mediate protection against lethal challenge with ST3 pneumococcus in mice but do not promote phagocytic killing in vitro (nonopsonic antibodies) have been described. In this study, we sought to determine the biological activity of one such MAb, A7 (a human PPS3-specific IgM), and the mechanism by which it mediates protection. In vitro studies demonstrated that coincubation of A7 with ST3 in the absence of phagocytes or a complement source resulted in a reduction in CFU on blood agar plates that was largely reversible by sonication. A chromogenic cellular proliferation assay demonstrated that A7 did not affect replication of ST3 in liquid culture. The ability of A7 to induce aggregation of ST3 was confirmed by fluorescence microscopy and flow cytometry: A7 induced aggregation of ST3, and in the presence of a complement source, A7 promoted deposition of complement component 3 (C3) on aggregated bacteria in a dose-dependent fashion. Similarly, administration of preincubated mixtures of A7 and ST3 intraperitoneally to mice protected them from the lethality of ST3 in a dose-dependent fashion. These findings suggest that A7-mediated aggregation enhances resistance to ST3, most likely by enhancing C3 deposition on the ST3 capsule, thereby promoting host antipneumococcal activity in vivo.Despite the availability of antibiotics and two vaccines for Streptococcus pneumoniae (pneumococcus), mortality attributable to pneumococcal disease remains a significant global problem (1, 23). Concerns about ongoing pneumococcal antibiotic resistance, poor vaccine immunogenicity in immunocompromised patients, and serotype (ST) replacement stemming from use of the conjugate vaccine (23,25,29,38) underscore the critical need for a better understanding of correlates of pneumococcal immunity. The efficacy of pneumococcal capsular polysaccharide (PPS)-based vaccines has been linked to their ability to elicit serotype-specific IgG that promotes phagocytosis and killing of the homologous pneumococcal ST in vitro (13,27,43,46). However, given that ST3 has emerged as a replacement ST that causes severe disease (23,25), it is concerning that an investigational conjugate vaccine containing an ST3 moiety did not protect against ST3 disease in children (37). The foregoing, together with evidence that ST3 is associated with a higher risk of severe disease and death than other serotypes (3,23,35), suggests the need for new strategies to prevent disease with ST3.