Modulation of adhesion molecules and monocyte chemoattractant protein by tumor necrosis factor-alpha and salicylic acid in primary human coronary artery endothelial cells.

Kawasaki disease (KD) is an illness characterized by vascular inflammation of coronary arteries leading to coronary aneurysms and thromboses. Infiltration of immune cells into the intima and adventitia are observed in autopsy tissues of patients with KD. Using semi-quantitative RT-PCR and cell-based ELISA, we demonstrated that tumor necrosis factor-a induced the expression of intercellular adhesion molecules-1 and E-selectin, as well as monocyte chemoattractant protein-1, in a time- and dose-dependent manner in primary human coronary artery endothelial cell cultures. This increase was inhibited by salicylic acid (NaSal), and involved the transcription factor NF-kappaB. Based on these data, we suggest a pathogenetic mechanism for KD, whereby immune cells are attracted to sites of inflammation, undergo extravasation, release enzymes that assist in vascular remodeling, thereby weakening the endothelium and hastening the process of aneurysm formation. NaSal, in addition to preventing thrombosis and lowering fever in KD, may also function in down-regulating adhesion molecules during the inflammatory stage of KD.

Fecal excretion of a novel human circovirus, TT virus, in healthy children.

The role of TT virus (TTV) as a human pathogen is unclear, as is the mode of TTV transmission. To determine the prevalence of TTV infection and the possible fecal-oral route of transmission, we analyzed fecal specimens from 67 healthy, nontransfused children for TTV DNA sequences by heminested PCR, using the NG and T primer sets. The overall prevalence of TTV fecal excretion was 22.4% (15 of 67), with the T primer set (19.4%) being more sensitive than the NG primer set (10.4%). TTV prevalence based on gender or ethnicity showed no significant differences. None of seven children in the 0- to 6-month age group had detectable TTV in feces. Of three sets of siblings, two unrelated sets of twins, ages 33 and 37 months, were negative for fecal TTV DNA, while the third set of siblings, ages 99 and 35 months, was positive. The absence of TTV in the feces of children younger than 6 months and the high prevalence (40%) in children 7 to 12 months of age is consistent with age-specific acquisition of TTV infection by the nonparenteral route. TTV genotypes 1, 3, 4, and 5 were represented in our study population. TTV-positive siblings had TTV genotypes 1 and 4, suggesting unrelated environmental sources of TTV infection. This observation suggests a possible time frame for TTV acquisition in children which coincides with increased interaction with their environment and increased susceptibility to infectious agents.

Lack of association between acquisition of TT virus and risk behavior for HIV and HCV infection in Vietnam.

BACKGROUND: The search for the cause of chronic hepatitis among individuals with non-A to G hepatitis has led to the discovery of a post-transfusion hepatitis-related DNA virus, designated TT virus (TTV), which, based on viral sequences, belongs to a new virus family. The principal modes of infection with TTV are poorly understood, and its role in human immunodeficiency virus type 1 (HIV-1) infection is unclear. OBJECTIVE: To determine if injection drug use (IDU) and high-risk heterosexual activity (HRHA), principal modes of acquiring HIV-1 infection, place individuals at greater risk of acquiring TTV. METHODS: The authors analyzed DNA, extracted from sera or filter paper-blotted whole blood, obtained during August 1997 and June 1998 from 324 Vietnamese (148 male; 176 female), for TTV sequences by hot-start, heminested polymerase chain reaction. RESULTS: Prevalence of TTV viremia was similar among individuals engaging in IDU or HRHA (23.4% vs. 20.2%; P > 0.5), with no age- or gender-specific differences. No association was found between TTV viremia and co-infection with HIV-1 or hepatitis C virus (HCV). Phylogenetic analysis of 30 TTV sequences revealed two distinct genotypes and four subtypes that did not segregate according to gender, HIV-1 and HCV risk behaviors, or geographic residence. CONCLUSIONS: Among HIV-1- or HCV-infected Vietnamese, who presumably acquired their infection by either the parenteral or nonparenteral route, the data indicate no clear association between acquisition of TTV infection and risk behavior for HIV-1 or HCV infection, suggesting that the usual route of TTV transmission in Vietnam is other than parenteral or sexual.

High prevalence of GB virus C/hepatitis G virus infection among homosexual men infected with human immunodeficiency virus type 1: evidence for sexual transmission.

GB virus C/hepatitis G virus (GBV-C/HGV), a recently discovered orphan flavivirus, is distantly related to hepatitis C virus (HCV). Although both GBV-C/HGV and HCV can be transmitted by the parenteral route, their principal modes of transmission and associated risk behaviors may differ. Using reverse transcription-polymerase chain reaction, the 5'-noncoding regions of GBV-C/HGV and HCV were amplified from plasma or sera of 209 individuals infected with human immunodeficiency virus type 1 (HIV-1). As verified by Southern blot analysis, GBV-C/HGV and HCV infection were detected in 37 (17.7%) and 22 (10.5%) of 209 HIV-1-infected individuals, respectively. GBV-C/HGV infection was significantly associated with homosexual sex (P = 0.044) and was more common than HCV infection among HIV-1-infected homosexual men (P = 0.006). The prevalence of GBV-C/HGV infection was nearly equal in women infected with HIV-1 via high-risk heterosexual sex (14.0%) or injection drug use (IDU) (17.5%). By contrast, HCV infection was associated significantly with women reporting IDU when compared to women reporting high-risk heterosexual sex (P < 0.0001). Alanine aminotransferase levels were elevated in HIV-1-infected individuals who were co-infected with HCV (P = 0.009), but not with GBV-C/HGV (P = 0.9). The high prevalence of GBV-C/HGV infection in HIV-1-infected nondrug-injecting homosexual men and among women engaging in high-risk heterosexual sex is consistent with transmission by the mucosal route and with acquisition of infection by the receptive rather than insertive partner.

Gradual loss of IgG antibodies against GB virus C/hepatitis G virus in a patient with AIDS.

GB virus C/hepatitis G virus (GBV-C/HGV) is a positive-sense, single-stranded RNA virus belonging to the family Flaviviridae and is distantly related to hepatitis C virus (HCV). GBV-C/HGV can be transmitted by the parenteral and the sexual route. Among individuals infected with human immunodeficiency virus type 1 (HIV-1) by the sexual route, we and others have demonstrated a high prevalence of GBV-C/HGV infection. Recently, Woolley and colleagues reported that AIDS patients co-infected with GBV-C/HGV had a significantly lower mean CD4 cell count than AIDS patients without GBV-C/HGV infection, suggesting that GBV-C/HGV antibody may be lost with progression to AIDS. To our knowledge no data are available on the loss of antibody against GBV-C/HGV in AIDS patients. We now report on an HIV-infected patient who exhibited gradual loss of IgG antibodies against GBV-C/HGV, as well as HCV, with progression of HIV disease.

An autocrine/paracrine role of human decidual relaxin. I. Interstitial collagenase (matrix metalloproteinase-1) and tissue plasminogen activator.

Decidual and placental relaxins have been proposed as autocrine/ paracrine hormones in the remodeling of collagen in the amnion and chorion in the last weeks of pregnancy. The matrix metalloproteinase-1 (MMP-1) is a key enzyme in the degradation of the interstitial collagens which predominate in the fetal membranes. Distribution of the MMP-1 gene and of the MMP-1 protein was shown by in situ hybridization and immunolocalization, respectively, in amnion, chorion, and decidua collected from patients before the onset of spontaneous labor. The distribution of MMP-1 in the chorionic cytotrophoblast and decidua coincided with that of the human relaxin receptor, detected by tissue section autoradiography in tissues collected at the same stage of pregnancy. Fetal membrane explants were used to study the effect of exogenous human relaxin H2. These responded by a dose-dependent increase in expression of the MMP-1 gene, in its secreted protein, and in its enzyme activity in the medium. A similar dose-dependent increase in the tissue plasminogen activator (tPA) gene and protein upon exposure of the explants to relaxin H2 suggested a coordinated cascade system, resulting in increases in secreted activities of MMP-1, MMP-3 (stromelysin), and MMP-9 (gelatinase B). There was no effect on the genes or proteins for MMP-2 (gelatinase A) or tissue inhibitor of metalloproteinase-1 (TIMP-1), showing the specificity of the response. This coordinated regulation by relaxin H2 of tPA, MMP-1, MMP-3, and MMP-9 would result in more complete degradation of the fetal membrane extracellular matrix components.

An autocrine/paracrine role of human decidual relaxin. II. Stromelysin-1 (MMP-3) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1).

Interstitial collagen types I and III are the predominant collagens in the amniotic and chorionic connective tissues. However, this matrix also contains proteoglycans, fibronectin, laminin, and elastin, which together with the collagens may undergo partial degradation prior to fetal membrane rupture at term. In this study, stromelysin (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were immunolocalized in fetal membranes obtained at term prior to labor. MMP-3 stained the cells of the amniotic epithelium, fibroblasts and macrophages of the amniotic and chorionic matrix, and those of the chorionic cytotrophoblast; there was no staining in the maternal decidua. TIMP-1 showed a similar staining pattern, except that the staining was darker in some amniotic epithelial cells and was present in the maternal decidua. The maternal decidua produces the two human relaxins H1 and H2; the latter, when incubated with explants of human fetal membranes, caused a dose-dependent and significant increase in expression of the MMP-3 gene and its secreted protein into the media. A significant effect of relaxin H2 on 92-kDa gelatinase (MMP-9) gene expression was also shown--an effect requiring poly(A)+ RNA rather than total RNA. Both relaxin H1 and H2 caused a significant increase in secretion of MMP-9 protein and its enzyme activity in the media. The magnitude of the effects of the two relaxins was similar, in contrast to findings from other biological studies in which relaxin H2 was shown to be more active. Neither of the relaxins had any effect on 72-kDa gelatinase (MMP-2) activity or on the TIMP-1 protein or its activity. This study suggests that local relaxins may be involved in the degradation of the complex fetal membrane extracellular matrix and may cause activation of an enzyme cascade resulting in fully activated MMP-9. Such effects could be important in the degradative pathways occurring in the amnion and chorion in the peripartal period.