左旋氧氟沙星对大鼠血胰屏障的通透性

目的 :研究左旋氧氟沙星对大鼠血胰屏障的通透性。方法 :经尾静脉推注左旋氧氟沙星 (2 0mg·kg 1体重 ) ,在规定的时间点取样 ,用高效液相色谱法 (HPLC)测定胰腺、肝脏组织和血清中药物的含量。结果 :在大鼠血清中的左旋氧氟沙星浓度在5min时最高 ,为 2 0 .2 47μg·mL 1,胰腺、肝脏组织都在 10min时最高分别 2 1.85 0 μg·g 1、30 .5 90 μg·g 1,然后持续下降 ;10min时胰组织的药物浓度开始高于血清 ,90min后两者浓度接近。药物对血胰屏障的通透率 (PR)在 5min时 0 .85 ,然后处于上升趋势 ,2 0min时最高达到 3 .82 ,然后下降 ,90min后接近 1。结论 :静脉推注左旋氧氟沙星后 ,药物对血胰屏障具有良好的通透性 ,值得向临床推荐预防和治疗胰腺感染。     

Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines

Development of a herpes simplex virus (HSV) vaccine is a priority because these infections are common. It appears that potent adjuvants will be required to augment the immune response to subunit HSV vaccines. Therefore, we evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant in a mouse model of genital herpes. Using a whole-virus vaccine (HVAC), we showed that the addition of CLDC improved antibody responses compared to vaccine alone. Most important, CLDC increased survival, reduced symptoms, and decreased vaginal virus replication compared to vaccine alone or vaccine administered with monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) following intravaginal challenge of mice. When CLDC was added to an HSV gD2 vaccine, it increased the amount of gamma interferon that was produced from splenocytes stimulated with gD2 compared to the amount produced with gD2 alone or with MPL-alum. The addition of CLDC to the gD2 vaccine also improved the outcome following vaginal HSV type 2 challenge compared to vaccine alone and was equivalent to vaccination with an MPL-alum adjuvant. CLDC appears to be a potent adjuvant for HSV vaccines and should be evaluated further.Herpes simplex virus type 1 (HSV-1) and HSV-2 are two members of the HSV family of alphaherpesviruses, which establish lifelong latent infection in sensory neurons and lead to chronic herpes disease. HSV-1 infection causes facial/ocular disease, while HSV-2 is the leading cause of genital herpes, although both viruses can be found at oral and genital sites. Indeed, the incidence of HSV-1 genital disease is increasing and approximates that of HSV-2 in certain countries (17). Approximately 45 million people in the United States (20 to 30%) have genital herpes infection, and new infections occur at a rate of 1 million per year (17, 29). One of the most serious complications of genital herpes occurs when the virus is transmitted from mother to neonate. Infection of the neonate causes significant morbidity and mortality, even with proper antiviral therapy (25). Genital herpes infection also increases the risk of acquiring human immunodeficiency virus (HIV) infection and increases shedding of HIV in genital lesions (5, 40).HSV-2 infection induces both humoral and T-cell-mediated immunity; however, the mechanisms that contribute to long-term control of genital herpes are not understood and could be different from those that will protect against primary infection or disease. Studies from animal models of HSV infection and human studies indicate that high levels of neutralizing antibodies, innate immunity natural killer (NK) cells, interferon (IFN), and macrophages contribute to protection from HSV infection, but the major determinants of HSV protection are both CD8⁺ and especially CD4⁺ T cells (7, 9, 23, 27, 30, 31). Clearance of virus from recurrent lesions is also more closely correlated to T-cell immunity. Thus, when a recurrent lesion occurs, mononuclear cells, primarily CD4⁺ T cells, infiltrate the lesion as early as 2 days after formation and are followed by an influx of CD8⁺ T cells at later times (10). Although both HSV-specific CD4⁺ and CD8⁺ T-cell responses are detected, clearance of HSV-2 from lesions correlates with a CD8⁺ cytotoxic T lymphocyte response (27, 45).Vaccines for genital herpes have a long history, beginning in the 1940s, but only recently have some HSV-2 subunit vaccines shown partial efficacy in human trials (reviewed in reference 35). A gD2 vaccine (GlaxoSmithKline) formulated with a mixture of alum and 3-deacylated monophosphoryl lipid A (MPL) prevented clinical symptoms of primary HSV-2 infection (approximately 70% efficacy), but only in women who were HSV-1 and HSV-2 seronegative before vaccination (38). Protection against HSV-2 infection was approximately 40% in the HSV-seronegative women. The vaccine did not provide protection in men or in women who were previously infected with HSV-1. Another vaccine consisting of gD2 and gB2 formulated with the adjuvant MF-59 (Chiron) induced a strong neutralizing antibody and CD4⁺ T-cell proliferative responses but did not decrease primary genital infections or the frequency of subsequent recurrences (8). However, it should be pointed out that the results for this vaccine were not analyzed for protection only in HSV-1-seronegative women, thus making comparisons with the gD2 vaccine discussed above difficult. Some have attributed differences in the Chiron and GSK vaccines to the adjuvant used in the vaccines, thus highlighting the importance of adjuvants for HSV vaccines (9, 26).Cationic liposome-DNA complexes (CLDC) were originally developed as a system of gene delivery of bacterial plasmid DNA for potential gene therapy (46). However, as part of preclinical and phase I studies of this technology, it became apparent that intravenous administration of CLDC profoundly activated innate immunity and inhibited gene expression. CLDC administration resulted in the release of particularly high circulating levels of alpha IFN (IFN-α), suggesting potent activation of plasmacytoid dendritic cells (DC), and interleukin-12, suggestive of conventional DC activation (11, 12, 15). This activation was independent of whether the plasmid contained any cDNA coding region (the “empty-vector” effect) and has subsequently been shown to occur with Toll-like receptor 3 (TLR3) agonists as well when the same mixture of cationic and neutral lipids is used (44). The empty-vector DNA used for CLDC gene therapy contains multiple unmethylated CpG motifs, and part of the robust induction of innate immunity is likely to reflect the internalization of the DNA into the endosomes of plasmacytoid DC, where these CpG motifs can engage TLR9. Further, addition of peptide or protein antigens to CLDC created a very potent adjuvant effect, with elicitation of strong T-cell and antibody responses (44). We therefore evaluated the use of CLDC as an adjuvant for a genital herpes vaccine using the well-established mouse model.     

经冠状动脉造影证实的初次冠状动脉支架内血栓形成长期临床预后:431例临床分析

<正>本研究(Dutch Stent Thrombosis Registry)为一项多中心研究,纳入了2004年1月至2007年2月期间经造影确认的ST病例。本研究ST的定义根据ARC分类为明确的血栓形成。根据事件发生的时间分为急性(24 h之内)、亚急性(24h～30 d)、晚期(30 d～1年)和极晚期(1年以后)血栓形成。临床随访采用电话方式询问患者、亲属及家庭医生,或从药房、医院记录获得患者情况。随访内容为主要不良心血管事件(MACE)的发生率(包括死亡、再发ST、心肌梗死和冠状动脉重建术)。研究的一级终点为心源性死亡和明确的再发ST(ARC分类);二级终点为全因死亡、心源性死亡、再发明确的ST、再发明确的或可能的ST、靶血管或非靶血管相关的心肌梗死和任何缺血驱使的靶血管血运重建。共437例患者有明确ST纳入本研究。其中6例因既往曾有ST而被剔除。第1次发生明确ST的431例患者中,140例为急性ST[占总数的32.5%,占金属裸支架(BMS)的33%,占药物洗脱支架(DES)的30%],177例为亚急性ST(占总数     

Establishment and characterization of a primary effusion (body cavity- based) lymphoma cell line (BC-3) harboring kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus

The recently identified Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), has been found to be consistently associated with an unusual subset of acquired immunodeficiency syndrome-related lymphomas, the so-called body cavity- based lymphomas (BCBL) or primary effusion lymphomas (PEL). These lymphomas are characterized by a unique spectrum of morphologic and molecular characteristics, and grow as lymphomatous effusions without an identifiable contiguous tumor mass. Until now, efforts to delineate the role of KSHV in the pathogenesis of PELs have been hampered by the lack of appropriate model systems and the concomitant presence of Epstein-Barr virus (EBV) in nearly all cases examined, and in all previously established cell lines. We now report the establishment and characterization of a novel PEL cell line, BC-3, which is KSHV+ by polymerase chain reaction (PCR) but EBV- as assessed by a variety of methods including PCR for EBER, EBNA-2, and EBNA-3C. This cell line was established from a lymphomatous effusion obtained from an HIV- patient, and has immunophenotypic and molecular features consistent with the diagnosis of PEL, including an indeterminate immunophenotype with a B- cell immunogenotype and lack of c-myc proto-oncogene rearrangements. Pulsed-field gel electrophoresis shows an intact KSHV genome of about 170 kb both in the cell line and in the viral isolate, whereas herpesvirus-like capsids are visible by electron microscopy. Consequently, the BC-3 cell line represents an invaluable tool as a source of KSHV, for both the evaluation of the pathogenic potential of this virus and the mechanistic characterization of its role in the development of Kaposi's sarcoma and malignant lymphoma.     

Emergence of B-immunoblastic sarcoma in patients with multiple myeloma: a clinicopathologic study of 10 cases

Immunologic and histologic studies were performed in 10 cases of myeloma that showed progression to a more aggressive proliferation, designated as immunoblastic sarcoma of B-cell type (B-IBS). Several patterns of clinical presentation were observed: eight patients showed typical multiple myeloma, four developed B-IBS within the bone marrow, and four developed B-IBS in multiple extramedullary sites; the remaining two patients had relatively localized myeloma, but also showed development of extramedullary B-IBS. The implications of these findings are discussed with regard to their prognostic import and their relationship to current concepts of plasma cell development.