Protection against Plasmodium chabaudi malaria induced by immunization with apical membrane antigen 1 and merozoite surface protein 1 in the absence of gamma interferon or interleukin-4

Strategies to optimize formulations of multisubunit malaria vaccines require a basic knowledge of underlying protective immune mechanisms induced by each vaccine component. In the present study, we evaluated the contribution of antibody-mediated and cell-mediated immune mechanisms to the protection induced by immunization with two blood-stage malaria vaccine candidate antigens, apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP-1). Immunologically intact or selected immunologic knockout mice were immunized with purified recombinant Plasmodium chabaudi AMA-1 (PcAMA-1) and/or the 42-kDa C-terminal processing fragment of P. chabaudi MSP-1 (MSP-1(42)). The efficacy of immunization in each animal model was measured as protection against blood-stage P. chabaudi malaria. Immunization of B-cell-deficient JH(-/-) mice indicated that PcAMA-1 vaccine-induced immunity is largely antibody dependent. In contrast, JH(-/-) mice immunized with PcMSP-1(42) were partially protected against P. chabaudi malaria, indicating a role for protective antibody-dependent and antibody-independent mechanisms of immunity. The involvement of gammadelta T cells in vaccine-induced PcAMA-1 and/or PcMSP-1(42) protection was minor. Analysis of the isotypic profile of antigen-specific antibodies induced by immunization of immunologically intact mice revealed a dominant IgG1 response. However, neither interleukin-4 and the production of IgG1 antibodies nor gamma interferon and the production of IgG2a/c antibodies were essential for PcAMA-1 and/or PcMSP-1(42) vaccine-induced protection. Therefore, for protective antibody-mediated immunity, vaccine adjuvants and delivery systems for AMA-1- and MSP-1-based vaccines can be selected for their ability to maximize responses irrespective of IgG isotype or any Th1 versus Th2 bias in the CD4(+)-T-cell response.     

Human and murine lymphocyte neurotrophin expression is confined to B cells

Recent reports indicate that autoreactive T cells may produce neurotrophic factors capable of mediating repair and regeneration of damaged neurons. By using semiquantitative RT-PCR, we examined gene expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and the trkB BDNF receptor in autoreactive T cells from SWXJ mice immunized with the p104-117 encephalitogen of myelin proteolipid protein (PLP 104-117). We observed antigen-inducible expression of NGF and BDNF, but not NT-3 and trkB, in lymph node cells activated with PLP 104-117. To determine which leukocyte subpopulation expressed neurotrophins, CD4(+), CD8(+), B220(+), CD11b(+), and NK1.1(+) cells were purified from activated primary cultures, and their mRNAs were analyzed. Neurotrophin expression was also measured in CD3(+) T cells purified from mouse CNS during acute onset of experimental autoimmune encephalomyelitis as well as in resting and activated human T cells and B cells purified from peripheral blood of normal subjects. In all cases, we found that neurotrophin expression was confined exclusively to B cells (B220(+)) in both mouse and human. CD3(+), CD4(+), and CD8(+) T cells as well as NK1.1(+) cells and CD11b(+) monocytes and macrophages did not express any detectable BDNF, NGF, NT-3, or trkB under any conditions. Our data indicate that B cells rather than T cells are the predominant if not the only source of leukocyte-derived neurotrophins and as such may provide "protective autoimmunity" in repair and regeneration of the injured nervous system.     

Image guided I125 prostate brachytherapy with Hybrid Interactive Mick technique in the community setting: How does it compare?

The aim of this study is to evaluate the target coverage, procedural techniques, and merits of Hybrid Interactive Mick (HIM) I125 transperineal permanent implantation (TPPI) of the prostate performed with 10 urologists in a community hospital. Detailed day 0 post-implant dosimetric evaluations of TPPI procedures were performed on 333 consecutive monotherapy patients treated between September 2000 and November 2003 at a single institution. All patients underwent TPPI with HIM. Pelvic and CXR films were obtained for a manual seed count at day 0 and again > day 90 on 175 patients. The HIM-prostate brachytherapy performed in a community hospital provided median D(90), V100, and V150 values of 157Gy, 94%, and 42.3%, respectively. 18% of patients had seed migration to the lungs while 2% had seed migration to the bladder. Only 7 patients (4%) had 2 or more seeds migrate to the lungs. Procedure times average 38 minutes and number of needles used averaged 18. The post-implant urinary retention rate was 2.1% Use of HIM-prostate brachytherapy in the community setting with multiple urologists reproducibly maintained excellent and consistent dosimetric coverage. Procedure times and number of needles used were minimized, and with careful attention to image-guided technique, seed migration to bladder and lung was also minimized.     

Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study

OBJECTIVE: Selective estrogen receptor modulators are novel compounds that bind to the estrogen receptor and have mixed agonistic and antagonistic activities. Recently, an increase in urinary incontinence has been reported with hormone replacement therapy use. A decrease in surgical procedures for pelvic floor relaxation has been recently reported with raloxifene, a selective estrogen receptor modulator that is not uterotropic. Levormeloxifene is a selective estrogen receptor modulator that was developed for the purpose of the treatment and prevention of postmenopausal osteoporosis. STUDY DESIGN: This was a multicentered prospective study of healthy women aged >or=65 years with osteoporosis who were randomized to blindly receive placebo or levormeloxifene 0.5 mg or 1.25 mg daily as part of a planned 3-year osteoporosis treatment study. Multiple medical and gynecologic evaluations were performed. Adverse events were reported to investigators and coded with the use of World Health Organization terminology. This study was halted after 10 months because of the large number of gynecologic and other adverse events. RESULTS: Among 2924 women who were studied, those women who were treated with levormeloxifene had a marked increase compared with placebo in leukorrhea (30% vs 3%), increased endometrial thickness on ultrasound scan (19% vs 1%), enlarged uterus (17% vs 3%), uterovaginal prolapse (7% vs 2%), urinary incontinence (17% vs 4%), increased micturition frequency (9% vs 4%), lower abdominal pain (17% vs 6%), hot flushes (10% vs 3%), and leg cramps (6% vs 0.8%). All of these differences were highly statistically significant with a probability value of.0001 for each. CONCLUSION: Levormeloxifene results in multiple adverse gynecologic and other events in postmenopausal women with osteoporosis.