Natural Antibody Contributes to Host Defense against an Attenuated Brucella abortus virB Mutant

Brucella abortus is an intracellular pathogen that persists within phagocytic cells of the reticuloendothelial system. To identify in vivo interactions between B. abortus and the host that lead to persistent infection, we studied the persistence of B. abortus and an isogenic virB mutant deficient in the VirB type IV secretion system (T4SS) in knockout mice. In contrast to control mice, mice lacking B cells (Igh6^−/−) were permissive for infection with the attenuated virB mutant. To determine the basis for this phenotype, we characterized immune functions of Igh6^−/− mice in the context of B. abortus infection. Igh6^−/− mice had greater numbers of extracellular bacteria in the spleen and increased early expression of proinflammatory cytokines during B. abortus infection. Further, a virB mutant, despite its wild-type level of survival, failed to elicit microgranuloma formation in the spleens of Igh6^−/− mice, suggesting a requirement for the T4SS to elicit this pathological change. Passive transfer of immunoglobulin G from naïve mice restored the ability of Igh6^−/− mice to control the persistence of the virB mutant by a complement-independent mechanism. Further, adoptive transfer of CD11b⁺ cells from C57BL/6 mice to Igh6^−/− mice restored the ability of the knockout mice to limit the replication of the virB mutant in the spleen, suggesting that the Igh6^−/− mutation affects phagocyte function and that phagocyte function can be restored by natural antibody.Human brucellosis is a febrile disease resulting from the transmission of Brucella abortus, B. suis, B. melitensis, or B. canis from its respective zoonotic reservoir in cattle, swine, goats and sheep, or dogs (47). These pathogens are endemic in many areas of the world, including Central and South America, the Mediterranean, and Central Asia, and are responsible for an estimated 500,000 new brucellosis cases each year (1). In human brucellosis, as well as in the zoonotic reservoir species, bacteria may persist for long periods of time in the reticuloendothelial system (7). This aspect of infection can be modeled in the mouse, which has been used to identify and characterize the virulence factors involved in the systemic persistence of Brucella spp. (2, 22).One essential virulence factor of the human pathogenic Brucella species is the type IV secretion system (T4SS) encoded by the virB locus on chromosome II (18, 29, 40). The T4SS of Brucella spp., similar to those of other bacterial pathogens, mediates the translocation of proteins into host cells; however, the functions of two newly identified B. abortus T4SS substrates, VceA and VceC, is not yet known (12, 25, 39, 45, 46). In cultured macrophages and dendritic cells (DC), the T4SS is essential for the intracellular replication and persistence of B. abortus (13, 36, 40). The T4SS mediates exclusion of late endosomal/lysosomal markers from the Brucella-containing vacuole and targeting of B. abortus to exit sites of the endoplasmic reticulum, where replication occurs (5, 6, 12, 41), suggesting that T4SS effectors are involved in this function. After intraperitoneal (i.p.) inoculation of mice, the T4SS is required not for the initial systemic dissemination of B. abortus but rather for persistence in the reticuloendothelial system (31, 34). In order to better understand the interactions between the host and B. abortus that lead to the persistence of wild-type (WT) strains and the eventual clearance of virB mutants, we examined the immune mechanisms required for clearance of the virB mutant. Unexpectedly, mice lacking B cells (Igh6^−/−) were permissive for the splenic persistence of the virB mutant, while the persistence of WT B. abortus was not increased. When cultured ex vivo, macrophages from Igh6^−/− mice behaved identically to macrophages from control mice in their ability to control the intracellular replication of the virB mutant while permitting the replication of WT B. abortus (34).In this study, we attempted to pinpoint the defect in Igh6^−/− mice that renders them permissive for persistent infection by the virB mutant. Our results show that nonspecific antibody can reverse the defect of these mice in controlling virB mutant replication without affecting WT B. abortus. These results suggest that the T4SS mediates the evasion of a natural antibody-dependent immune clearance function by B. abortus during persistence in vivo.     

Brucella abortus virB12 is expressed during infection but is not an essential component of the type IV secretion system

The Brucella abortus virB operon, consisting of 11 genes, virB1 to virB11, and two putative genes, orf12 (virB12) and orf13, encodes a type IV secretion system (T4SS) that is required for intracellular replication and persistent infection in the mouse model. This study was undertaken to determine whether orf12 (virB12) encodes an essential part of the T4SS apparatus. The virB12 gene was found to encode a 17-kDa protein, which was detected in vitro in B. abortus grown to stationary phase. Mice infected with B. abortus 2308 produced an antibody response to the protein encoded by virB12, showing that this gene is expressed during infection. Expression of virB12 was not required for survival in J774 macrophages. VirB12 was also dispensable for the persistence of B. abortus, B. melitensis, and B. suis in mice up to 4 weeks after infection, since deletion mutants lacking virB12 were recovered from splenic tissue at wild-type levels. These results show that VirB12 is not essential for the persistence of the human-pathogenic Brucella spp. in the mouse and macrophage models of infection.     

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18,000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.     

Embolization of spinal cord arteriovenous shunts: morphological and clinical follow-up and results--review of 69 consecutive cases

OBJECTIVE: We sought to analyze the results of embolization in patients with intradural spinal cord arteriovenous shunts. METHODS: The clinical and radiological files of 69 of a population of 155 patients treated with embolization between 1981 and 1999 were reviewed retrospectively. The patients' clinical status was evaluated according to Karnofsky Performance Scale score. Twenty-one (14%) of 155 patients were treated surgically because they were thought to be poor candidates for embolization. Twenty-four (15%) of 155 patients were considered untreatable with surgery or embolization; in these patients, follow-up was proposed, but only 8 of them were followed appropriately and remained stable after the first consultation. Forty-one (26%) of 155 patients consulted our group, but no follow-up could be obtained. In 69 (45%) of 155 patients, comprising 20 children and 49 adults, endovascular treatment was performed with the patients under general anesthesia and without provocative tests, mainly with acrylic glue, in 99% of these patients. RESULTS: The mean number of diagnostic and therapeutic sessions was 3.5 per patient, and the mean number of pure therapeutic sessions was 1.5 per patient. Follow-up ranged between 6 months and 18 years (mean, 5.6 yr). In 16% of patients, anatomic obliteration of spinal cord arteriovenous shunts was obtained. Embolization reduced more than 50% of the spinal cord arteriovenous shunts in 86% of cases. No recanalization was noted on follow-up angiograms. Good clinical outcomes were obtained in 83% of the patients: 15% of them were asymptomatic, 43% were improved, and 25% were stable. In 4% of patients, embolization failed to stabilize the disease. Transient deficits were seen after embolization in 14% of the patients, and permanent severe complications occurred in 4% of the patients (Karnofsky Performance Scale score 相似文献   

Outcomes for women with co-occurring disorders and trauma: program and person-level effects

Six-month outcomes are evaluated from a 9-site quasi-experimental study of women with mental health and substance use disorders who have experienced physical or sexual abuse who enrolled in either comprehensive, integrated, trauma-informed, and consumer/survivor/recovering person-involved services (N = 1023) or usual care (N = 983). Mental health, post-traumatic stress symptoms, and substance use outcomes are assessed with multilevel regression models, controlling for program and personal characteristics. Person-level variables predict outcomes independent of intervention condition and, to a small extent, moderate intervention and program effects. In sites where the intervention condition provided more integrated counseling than the comparison condition, there are increased effects on mental health and substance use outcomes; these effects are partially mediated by person-level variables. These results encourage further research to identify the longer-term effects of integrated counseling for women with co-occurring disorders and trauma histories.     

Love,Trust, and HIV Risk Among Female Sex Workers and Their Intimate Male Partners

Objectives. We examined correlates of love and trust among female sex workers and their noncommercial male partners along the Mexico–US border.Methods. From 2011 to 2012, 322 partners in Tijuana and Ciudad Juárez, Mexico, completed assessments of love and trust. Cross-sectional dyadic regression analyses identified associations of relationship characteristics and HIV risk behaviors with love and trust.Results. Within 161 couples, love and trust scores were moderately high (median 70/95 and 29/40 points, respectively) and correlated with relationship satisfaction. In regression analyses of HIV risk factors, men and women who used methamphetamine reported lower love scores, whereas women who used heroin reported slightly higher love. In an alternate model, men with concurrent sexual partners had lower love scores. For both partners, relationship conflict was associated with lower trust.Conclusions. Love and trust are associated with relationship quality, sexual risk, and drug use patterns that shape intimate partners’ HIV risk. HIV interventions should consider the emotional quality of sex workers’ intimate relationships.While public health interventions continue to be grounded in tenets of risk and disease, there is growing recognition of the importance of emotions such as love and trust in shaping the health behaviors of diverse populations. Unprotected sex allows for transmission of HIV and other sexually transmitted infections (STIs) but often carries emotional meanings of trust and commitment that impede condom negotiation even among individuals with high knowledge and self-efficacy.1–4 Research has consistently found female sex workers’ condom use to be less frequent with their noncommercial male partners than with clients, which has been linked to intimacy, love, and trust.5–7 Similarly, drug-using couples may share syringes and engage in additional known HIV risk behaviors to convey support and emotional closeness.8,9 Although much of this research is qualitative, some quantitative work has confirmed associations between perceptions of intimacy and condom use among sex workers and clients10 and men who have sex with men.11Quantitative researchers have attempted to operationalize emotions into theoretical constructs for empirical research.12 Sternberg’s “triangular” theory posits that love comprises 3 components: intimacy (feelings of emotional closeness between partners), passion (physical attraction and sexual consummation), and commitment (decisions that partners make about maintaining relationships).13,14 Taken together, these components combine to generate different kinds of love.13,15,16Another important aspect of intimate relationships, trust is conceptualized as a belief in the integrity of a partner. Trust may be based on individuals’ assessments of their partners’ benevolence and honesty17 and subjective feelings of security within relationships.18,19 To measure trust quantitatively, Larzelere and Huston developed a dyadic trust scale that correlated with love and relationship quality.17A rich body of ethnographic scholarship has highlighted the importance of companionate relationships and love in diverse global contexts,20–22 but quantification of emotional constructs are largely absent from settings outside the Western middle-class experience. Most quantitative studies of love and trust have focused on privileged populations who do not experience the burden of disease that disproportionately affects socially marginalized couples. Existing studies among US populations have also suggested that women and men value components of these emotions differently,23–25 yet the implications of these potential gender differences for HIV prevention among vulnerable couples remains underexplored.Our study of love and trust among sex workers and their noncommercial partners is situated in 2 Mexican border cities: Tijuana, Baja California, south of San Diego, California (population 1.6 million), and Ciudad Juárez, Chihuahua, adjacent to El Paso, Texas (population 1.3 million). Both cities have areas where sex work and drug use are concentrated,26 lending to the conceptualization of the border as an HIV risk environment27 characterized by poverty, unemployment, violence, and availability of illicit drugs.28 Research has documented substantial overlap in risky sexual and injection drug use behaviors among marginalized female sex workers29 who often turn to sex work as a last option for supporting themselves and their dependents.30Drawing on Connell’s conceptualization of gender as a relational process influenced by structural and sociocultural factors,31 our previous qualitative and ethnographic inquiry into sex workers’ intimate partnerships in these cities proposed that emotions are shaped by the HIV risk environment of the border. Structural conditions bring partners together into relationships that provide critical material and emotional support. In light of limited economic opportunities, couples form tacit agreements regarding women’s engagement in sex work. In the process, women emerge as primary wage earners, alienating men from traditional gender roles as providers and shifting gender dynamics. To cope, partners mostly avoid communicating about sex work or disclosing HIV risk to protect the emotional integrity of the relationship.32We also found that these couples’ relationships range in emotional intensity from friendship and care to transformative experiences of love. Regardless, most couples demarcate their primary relationships from sex work by engaging in unprotected sex. Among couples who inject drugs, sharing syringes together (but not with others) often reinforces trust and care.33 Concerns of mistrust and infidelity also reduced couples’ interest in alternative HIV-prevention technologies such as pre-exposure prophylaxis.34In light of the central role of emotions in our qualitative research with these couples, we attempted to quantify constructs of love and trust and identify associated relationship traits and HIV risk behaviors in our larger cohort. We hypothesized that markers of relationship quality (e.g., higher satisfaction, lower conflict) and unprotected sex within primary relationships would be associated with higher love and trust, whereas extradyadic HIV risk behaviors (e.g., concurrent sexual partners, syringe sharing with others) would be associated with lower love and trust.     

西班牙渗出性老年性黄斑变性的相关流行病学因素(英文)

目的:报告在西班牙Castilla-Leo地区患有渗出性老年性黄斑变性(AMD)的样本人群的流行病学特点,并与一组来自同一地区和相同年龄人群进行比较。方法:在本次观察性前瞻性调查中,我们访问了在一家地区性诊所接受光动力学疗法的AMD患者。患者报告了高血压、高血脂、吸烟的病史,检查患者虹膜颜色并分为浅色(绿色、蓝色、灰色)和深色(淡褐色、褐色、黑色)。结果:共有343名患者接受了访问,平均年龄为74.9岁(55~93岁),其中64.5%为女性,35.5%为男性,有45.1%的患者虹膜颜色被划为浅色。这些患者中,有50%有动脉性高血压,15.3%接受高胆固醇血症治疗,30.2%吸烟或者已经戒烟(女性中占80.9%)。结论:在渗出性AMD患者中,虹膜颜色为浅色的频率较高。在我们的调查中,其他渗出性AMD其他的风险因素有男性的吸烟习惯、未接受高胆固醇血症治疗、患者为女性身份等。