Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response

Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4⁺ T cells in the lung. PA-specific CD4⁺ T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity.     

Effets d'un entraînement de type sprint sur les réponses catécholaminergiques à l'exercice bref et intense chez des adolescents

IntroductionThe purpose of this study was to evaluate the effect of sprint training on plasma catecholamine concentrations in response to a-6 second-sprint exercise in adolescent boys (GE). Moreover, to judge of the respective effects of training and pubertal maturation, we proposed the same protocol to a control group of adolescents (GT).ResultsHigher performances (P_max) were reported in GE after 6 months but did not change in CG. In response to sprint exercise, no change was found in maximal lactate concentrations (La_max) or in plasma noradrenaline concentrations (NA) in GE and GT. However, higher (A) responses were reported in GE and CG after the 6 seconds-sprint test and no difference was observed in this increase between the groups.ConclusionThese results suggest that in adolescent boys, sprint training may enhance performances but not catecholaminergic responses to short cycle ergometer sprinting.     

Costimulation and Autoimmune Diabetes in BB Rats

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55–120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.     

Rebleeding from a primary brain tumor manifesting as intracerebral hemorrhage (CNN 04/077, revised version)

Symptomatic spontaneous intratumoral hemorrhage is a rare event in a patient with a brain tumor (BT). Although the treatment of choice in such a case is surgical removal of both the tumor and the hemorrhage, the optimal timing for surgical intervention has not been clearly established, particularly in those who present with minimal neurological deficits and a small hemorrhage volume. Two cases of primary BTs manifesting as an intracerebral hemorrhage (ICH) are described, in which rebleeding from the tumor occurred shortly after the initial hemorrhage. The patients each presented with the sudden onset of a headache and minimal neurological deficits, and the neuroradiological workup was consistent with a diagnosis of hemorrhagic BT. Each patient remained neurologically stable, and elective surgery had been planned within 7 days of their admission, but rebleeding occurred 5 and 6 days, respectively, after admission. A BT manifesting as an ICH may rebleed shortly after the initial bleeding, and should be treated on an emergency basis instead of an elective basis regardless of the patient's neurological status on admission or hematoma volume on the initial CT scans.     

Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across large domains. Our results define direct targets of the MLL fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in cancer.     

Modification of the multiplex plasmid PCR assay for Borrelia miyamotoi strain LB-2001 based on the complete genome sequence reflecting genomic rearrangements differing from strain CT13–2396

The genome of Borrelia spp. consists of an approximate 1 megabase chromosome and multiple linear and circular plasmids. We previously described a multiplex PCR assay to detect plasmids in the North American Borrelia miyamotoi strains LB-2001 and CT13–2396. The primer pair sets specific for each plasmid were derived from the genome sequence for B. miyamotoi strain CT13–2396, because the LB-2001 complete sequence had not been generated. The recent completion of the LB-2001 genome sequence revealed a distinct number of plasmids (n = 12) that differed from CT13–2396 (n = 14). Notable was a 97-kilobase plasmid in LB-2001, not present in CT13–2396, that appeared to be a rearrangement of the circular plasmids of strain CT13–2396. Strain LB-2001 contained two plasmids, cp30–2 and cp24, that were not annotated for strain CT13–2396. Therefore, we re-evaluated the original CT13–2396-derived multiplex PCR primer pairs and determined their location in the LB-2001 plasmids. We modified the original multiplex plasmid PCR assay for strain LB-2001 to include cp30–2 and cp24. We also determined which LB-2001 plasmids corresponded to the amplicons generated from the original CT13–2396 primer sets. These observations provide a more precise plasmid profile based on the multiplex PCR assay and reflect the complexity of gene rearrangements that occur in B. miyamotoi strains isolated from the same geographic region.     

Factors affecting antibody responses to immunizations in infants born to women immunized against pertussis in pregnancy and unimmunized women: Individual-Participant Data Meta-analysis

BackgroundExploring factors that affect immune responses to immunizations in infants born to women immunized with tetanus-diphtheria-acellular-pertussis (Tdap) in pregnancy compared with unimmunized women is important in designing immunization programs.MethodsIndividual-participant data meta-analysis of 8 studies reporting post-immunization immunoglobulin G (IgG) levels to vaccine antigens in infants born to either women immunized with Tdap in pregnancy or unimmunized women, using mixed-effects models.ResultsIn infants of Tdap-immunized women, two-fold higher levels of anti-pertussis toxin (PT) and anti-diphtheria-toxoid (DT) IgG pre-primary immunization were associated with 9% and 10% lower post-primary immunization levels, (geometric mean ratio [GMR], PT: 0.91; 95% CI, 0.88–0.95,n = 494, DT: 0.9; 0.87–0.93,n = 519). Timing of immunization in pregnancy did not affect post-primary immunization anti-Bordetella pertussis, anti-tetanus-toxoid (TT) and anti-DT IgG levels. Spacing of infant immunization did not affect post-primary immunization anti-B. pertussis and anti-DT levels. In infants of Tdap-immunized women, two-fold higher levels of anti-PT and anti-filamentous haemagglutinin (FHA) IgG pre-primary immunization were associated with lower post-booster immunization levels, (GMR, PT: 0.91; 0.85–0.97,n = 224, FHA: 0.92; 0.85–0.99,n = 232). Timing of immunization in pregnancy did not affect post-booster immunization anti-Bordetella pertussis, anti-tetanus-toxoid (TT) and anti-DT IgG levels. Spacing of infant immunization did not affect post-booster immunization anti-PT, anti-pertactin (PRN), anti-TT and anti-DT IgG levels.In infants of unimmunized women, two-fold higher IgG levels of some vaccine antigens pre-primary immunization were associated with 8–17% lower post-primary immunization levels (GMR, PT 0.92, 95% CI:0.88–0.97, n = 373; FHA:0.88, 95% CI:0.85–0.92,n = 378; PRN:0.84, 95% CI:0.81–0.88, n = 367; TT:0.88, 95% CI:0.83–0.93, n = 241; DT: 0.83, 95% CI:0.79–0.87,n = 278). Two-fold higher levels of anti-FHA IgG pre-primary immunization were associated with 8% lower post-booster immunization levels (GMR, 0.92; 95% CI: 0.86–0.99,n = 138).DiscussionIncreased IgG levels pre-primary immunization is associated with reduced post-primary and post-booster immunization levels for some antigens in infants of women immunized or unimmunized in pregnancy, but their clinical significance is uncertain.