Infectious mononucleosis and B-cell transformation in response to infection with Epstein–Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1–470) gp350 protein (gp3501–470). Tetrameric gp3501–470 induced ∼20-fold higher serum titers of gp3501–470-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp3501–470. Further, epidermal immunization with plasmid DNA encoding gp3501–470 tetramer induced 8-fold higher serum titers of gp3501–470-specific IgG relative to monomer. Tetrameric gp3501–470 binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT)-specific CD4+ T-cell epitopes into the tetrameric gp3501–470 had no effect on the gp3501–470-specific IgG response in naïve mice, and resulted in suppressed gp3501–470-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp3501–470 is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest. 相似文献
PURPOSE OF REVIEW: The incidence and mortality of cardiovascular disease are increased in the context of rheumatoid arthritis. The purpose of this review is to examine our evolving understanding of the pathogenesis of cardiovascular disease in rheumatoid arthritis and to underscore the importance of tailored prevention of cardiovascular disease in this select population. RECENT FINDINGS: Recent reports have highlighted the shared pathobiology of cardiovascular disease and rheumatoid arthritis, both of which represent inflammatory disorders. Several reports have also provided much-needed insight into the deleterious impact that select therapies (including cyclo-oxygenase-2-specific inhibitors) may have in terms of the risk of cardiovascular disease in rheumatoid arthritis. Although further study is warranted, preliminary investigations also suggest that aggressive anti-inflammatory therapy, including the adjunctive use of statins, may play important cardioprotective roles in rheumatoid arthritis. SUMMARY: The pathogenesis of cardiovascular disease in rheumatoid arthritis is complex and involves several intermediate factors, including dyslipidemia, elevations in serum homocysteine, impaired insulin sensitivity, and endothelial dysfunction. Given the burden of cardiovascular disease in this population, it is important that health care providers caring for rheumatoid arthritis patients adopt a treatment course that is both comprehensive and individualized to address specific risk factors for cardiovascular disease. 相似文献
Novel star‐like polymers are prepared via atom transfer radical polymerization (ATRP) of polyhexamethylene guanidine hydrochloride (PHMG) macromonomer and acrylamide (AM) using β‐cyclodextrin (CD) with 8‐active and 5‐active sites as a macroinitiator. The resulting star‐like polymers are characterized by gel permeation chromatography (GPC) and 1H NMR and are used for deactivating bacteria and viruses. It is found that star polymers with comparable amounts of PHMG possess excellent antimicrobial activity, which, however, strongly depends on the topological structure (i.e., the arm number and the monomer ratio) of the composing copolymers. The in vitro antibacterial activities of the synthesized polymers are investigated against Escherichia coli in terms of the minimum inhibitory concentration (MIC), whereas the antiviral activity of star copolymers is assessed via a plaque assay against non‐enveloped adenovirus (ADV). The results show that the highest antimicrobial activity is achieved by the star‐like copolymer with the monomer ratio of 20:3 (AM:PHGM, mol/mol), while the number of functional arms is fixed at 8. The incorporation of PHMG also renders the star copolymer highly antiviral, thus permitting it to be used as an effective antibacterial/antiviral agent for various applications.
We examine progress towards the 1994 International Conference on Population and Development (ICPD) commitment to provide universal access to sexual and reproductive health (SRH) services by 2014, with an emphasis on changes for those living in poor and emerging economies. Accomplishments include a 45% decline in the maternal mortality ratio (MMR) between 1990 and 2013; 11.5% decline in global unmet need for modern contraception; ~21% increase in skilled birth attendance; and declines in both the case fatality rate and rate of abortion. Yet aggregate gains mask stark inequalities, with low coverage of services for the poorest women. Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 80 developing countries highlight persistent disparities in skilled birth attendance by household wealth: in 70 of 80 countries (88%), ≥80% of women in the highest quintile were attended by a skilled provider at last birth; in only 23 of the same countries (29%) was this the case for women in the lowest wealth quintile. While there have been notable declines in HIV incidence and prevalence, women affected by HIV are too often bereft of other SRH services, including family planning. Achieving universal access to SRH will require substantially greater investment in comprehensive and integrated services that reach the poor. 相似文献
To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation.
Methods
Participants included 55 adults (age 18–65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ≥2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1–3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25).
Results
Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO.
Conclusions
While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study. 相似文献