Search

To study whether replacement of nosocomial ampicillin-resistantRetrospective, matched-cohort study.The study included 20 Dutch and Danish hospitals from 2009 to 2014.Within the study period, 63 patients with VRE bacteremia (36 Dutch and 27 Danish) were identified and subsequently matched to 234 patients with ARE bacteremia (130 Dutch and 104 Danish) for hospital, ward, length of hospital stay prior to bacteremia, and age. For all patients, 30-day mortality after bacteremia onset was assessed.The risk ratio (RR) reflecting the impact of vancomycin resistance on 30-day mortality was estimated using Cox regression with further analytic control for confounding factors.The 30-day mortality rates were 27% and 38% for ARE in the Netherlands and Denmark, respectively, and the 30-day mortality rates were 33% and 48% for VRE in these respective countries. The adjusted RR for 30-day mortality for VRE was 1.54 (95% confidence interval, 1.06-2.25). Although appropriate antibiotic therapy was initiated later for VRE than for ARE bacteremia, further analysis did not reveal mediation of the increased mortality risk.Compared to ARE bacteremia, VRE bacteremia was associated with higher 30-day mortality. One explanation for this association would be increased virulence of VRE, although both phenotypes belong to the same well-characterized core genomic lineage. Alternatively, it may be the result of unmeasured confounding.

BackgroundIn many European hospitals, ampicillin-resistant Enterococcus faecium (ARE) is endemic, while outbreaks of vancomycin-resistant E. faecium (VRE), belonging to the same genetic lineage, are increasingly reported. We studied the attributable mortality due to vancomycin resistance in patients with E. faecium bacteremia and evaluated whether this is mediated by a delay in appropriate antibiotic therapy.MethodsIn a retrospective matched cohort study, patients with VRE bacteremia occurring between 2009 and 2014 in 20 Dutch and Danish hospitals were matched to patients with ARE bacteremia, on hospital, ward, length of hospital stay prior to bacteremia, and age. The risk ratio (RR) for 30-day mortality contrasting VRE with ARE was estimated with further analytic control for confounding factors.ResultsIn all, 63 VRE and 234 ARE episodes were matched (36 and 130 for the Netherlands and 27 and 104 for Denmark). Crude 30-day mortality was 27% and 38% for ARE in the Netherlands and Denmark, respectively, and 33% and 48% for VRE in the respective countries. The adjusted RR for 30-day mortality for VRE was 1.54 (95% confidence interval (CI) 1.06-2.25). Although appropriate therapy was initiated later for VRE than for ARE bacteremia, this did not appear to mediate the increased mortality risk.ConclusionsCompared to ARE bacteremia, VRE bacteremia was associated with higher 30-day mortality. One explanation for this association would be increased virulence of VRE, although both phenotypes belong to the same well-characterized core genomic lineage. Alternatively, it may be the result of unmeasured confounding.

Background This study sought to determine the incidence, risk factors, and characteristics of Staphylococcus ( S. ) aureus infections complicating percutaneous coronary interventions (PCI). Methods Between January 1999 and December 2002, 7640 PCI's were evaluated from 1 to 16 days post-PCI for the occurrence of a documented S. aureus infection. A case–control study was used to identify risk factors for the development of S. aureus infection in patients undergoing PCI. Results In total 21 S. aureus infections (0.27%) were documented at 1 to 16 days after the index PCI. The overall incidence of PCI-related infection was 0.14% (11 cases), 0.13% (10 cases) were intravascular line related. All 21 cases with S. aureus infections were matched with 63 controls randomly selected among patients who underwent a PCI but did not have S. aureus infections. Among the patients with S. aureus infections, the duration of hospital stay was significantly increased (24 vs 5 days). The overall mortality rate in the 21 patients with S. aureus infections was 4/21 [19%] (controls 2/42 [3%]). Congestive heart failure, alcohol abuse, emergency PCI, more than 1 PCI in three months and the presence of a sheath in the femoral artery and/or vein for the duration of more than 1 day after the procedure were independent risk factors for S. aureus infection after PCI. Conclusions S. aureus infection is a rare but potentially serious complication of PCI. Additional precautions should be considered in patients with these risk factors.

Previously we demonstrated a correlation between a nonsyncytium-inducing (NSI), non-T-cell line tropic phenotype of HIV-1 isolates and the capacity to replicate in primary monocyte-derived macrophages (MDM). Here we demonstrate that these NSI, monocytotropic HIV-1 isolates lack the capacity to replicate in two promonocytic cell-lines, HL60 and U937. In contrast, most syncytium-inducing (SI) HIV-1 isolates with tropism for T-cell lines and generally non-monocytotropic were able to establish a productive infection in promonocytic cell lines. Similar differences in tropism for monocytes and promonocytic cell lines were observed with infectious molecular clones. Our results indicate that virological studies on promonocytic cell lines do not necessarily pertain to the HIV-1 infection of monocytes in vivo.

Requirements for the establishment of productive infection with the human immunodeficiency virus type 1 (HIV-1) in primary monocytes were investigated. In vitro, monocytes rendered susceptible for infection after at least a 2-d culture, but when cultured in the presence of differentiation-inducing agent IL-4, accelerated susceptibility was seen. Complete resistance to HIV-1 infection was observed in monocytes that had been treated for 5 d with rIL-4, and comparable results were obtained with other differentiation inducers such as dexamethasone or 1,25(OH)2 vitamin D3 (1,25(OH)2vitD3). The inhibition of productive infection was not caused by downregulation of CD4 expression or HIV-1 transcription, nor by intracellular accumulation of virions. Since treatment with rIL-4, dexamethasone, or 1,25(OH)2vitD3 also resulted in complete inhibition of monocyte proliferation, we studied whether establishment of productive infection in monocytes is proliferation dependent. Irradiation or mitomycin-C treatment within 24 h after inoculation prevented productive HIV-1 infection of monocytes, suggesting a proliferation-dependent step early in the virus replication cycle. Polymerase chain reaction (PCR) analysis revealed the presence of only incomplete proviral DNA species in non-proliferating monocytes, indicating restriction of viral replication at the level of reverse transcription. Thus, in analogy with HIV-1 infection of CD4+ T cells, proliferation of monocytes during differentiation into macrophages is a prerequisite for productive infection with HIV.

The second and third variable domains (V2 and V3) of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope molecule have been shown to be determinants of syncytium-inducing (SI) capacity. Previously we have reported evidence that increased length of the V2 domain and duplication or relocation of potential N-linked glycosylation sites in V2 might be used as prognostic markers for evolution toward an SI phenotype. Here, we used a PCR assay that discriminates a 6-nucleotide difference in the length of the V2 domain, with a sensitivity of 1 elongated V2 domain when present in a background of 125 to 625 short V2 domains. Analysis of DNA isolated directly from PBMCs from 11 HIV-1-infected individuals prior to SI phenotype conversion revealed, however, that the usefulness of this PCR for V2 length polymorphism as predictive marker for SI phenotype evolution is limited. The strong association as observed in our previous study between elongation of the V2 domain and an SI phenotype prompted us to expand our first analysis. An extremely significant correlation was observed between V2 length and virus phenotype for samples obtained at about the moment of SI conversion, but not for samples obtained 3 to 35 months after SI phenotype conversion, suggesting that changes in V2 may be only transiently required to allow SI phenotype evolution. This possibly only transient nature of V2 elongation may explain the discrepancy between results by our group and others.

The predictive value of low T cell reactivity to CDR monoclonal antibodies for development of AIDS was evaluated and compared with low CD4 + cell numbers and the presence of syncytium-inducing human immunodeficiency virus (HIV) variants in 122 seropositive asymptomatic homosexual men for 4.5 years. Low T cell reactivity was a strong predictor for progression to AIDS in a multivariate proportional hazards analysis using these markers as covariates at entry and as time-dependent covariates. The combination of the three markers was associated with development of AIDS in 6 of 7 men within 15 months. In contrast, the group that lacked any of these markers had a very low risk (11%) for developing AIDS. In groups with one or two of these three markers, progression rates were 33% and 66%, respectively. These data demonstrate that measurement of T cell function in vitro is of value for staging of HIV infection and may be useful for monitoring therapy

The expression of human immunodeficiency virus type 1 (HIV-1) is enhanced after cell activation because of the interaction of cell-encoded nuclear factors that interact with binding sites in the long terminal repeats (LTRs). Here we studied the contribution of cell type-specific activation signals to differences in cytotropism of HIV-1 variants. Four closely related molecular HIV-1 clones with distinct biological phenotypes and different capacities to replicate in primary monocyte-derived macrophages (MDMs) or T cell lines were used. Sequence analysis of these LTRs revealed variation in functionally important regions. Adaptation of virus variants to particular host cells by differences in LTR responsiveness was analyzed. LTR-CAT constructs were transiently transfected in T cells that were stimulated with T cell-specific activation signals such as combinations of anti-CD3 or anti-CD28 MoAB or in primary monocytes that were stimulated with IL-3, IL-4, or GM-CSF. No differences in responsiveness to cell type-specific signals were demonstrated. To further elucidate the level of restriction in cell tropism, transfection of four full-length infectious molecular HIV-1 clones into 5-day cultured MDMs was performed. From all clones, competent virus could be rescued from MDMs by coculture with PHA-stimulated PBLs. However, following cell-free inoculation, proviral DNA could be detected by PCR analysis only in monocytes exposed to HIV-1 clones that previously were shown to establish productive infection.(ABSTRACT TRUNCATED AT 250 WORDS)

In asymptomatic human immunodeficiency virus (HIV) infection in humans, disturbed T cell functions such as anergy and programmed cell death, thought to result from inappropriate signaling by antigen-presenting cells due to HIV infection, precede increase in virus load, decline in CD4+ T cell numbers, and subsequent disease progression. Here, in 3 long-term HIV-1-infected asymptomatic chimpanzees, antigen-presenting cell function was intact and T cells had normal proliferative capacity with no evidence of HIV-1-associated programmed cell death. Polymerase chain reaction analysis demonstrated low frequencies of cells harboring proviral DNA. Primary virus isolation from the infected animals demonstrated the absence of monocytotropic HIV-1 variants, in concordance with complete insusceptibility of chimpanzee monocytes for HIV-1 infection. Possibly, because of the incapacity of HIV-1 to infect monocytes, systemic immune dysfunction will not occur, contributing to controlled viral replication and maintenance of the asymptomatic state in HIV-infected chimpanzees.

To study HIV-1 envelope-mediated syncytium formation we have amplified, cloned, expressed, and sequenced individual envelope genes from a set of eight biological HIV-1 clones. These clones were obtained from two patients and display either a syncytium-inducing (SI) or nonsyncytium-inducing (NSI) phenotype. Upon expression through recombinant vaccinia virus, individual envelope gene products display heterogeneous syncytium-inducing capacities which reflect the phenotype of the parental biological HIV-1 clones in all cases. For the eight biological HIV-1 clones presented here, variation of the envelope gene alone is sufficient to explain the observed variable syncytium-inducing capacity of the respective parental viruses. In addition we determined the complete nucleotide sequence of these envelope genes. The predicted amino acid sequence revealed a considerable amount of variation located mainly in the previously denominated variable regions. In various regions of envelope genes obtained from the same patient, phenotype associated amino acid variation was found. This phenotype associated amino acid variation however, is not conserved between the two sets of envelope genes derived from different patients. Four envelope sequences derived from clones obtained from one patient showed phenotype-associated amino acid variation in the fusion domain. Sequencing of 12 additional fusion domains revealed that this same variation is found in four additional clones. However, a functional test performed on recombinant vaccinia expressing mutant envelope genes showed that this observed fusion domain variation does not contribute to the variation in syncytium-inducing capacity of the envelope gene product.

Objective: To investigate the relation between detection of syncytium-inducing (SI), human immunodeficiency virus type 1 (HIV-1) variants, rate of CD4+ cell decline, and clinical progression. Desig...

Human immunodeficiency virus (HIV), the causative agent of AIDS, infects human lymphocytes and monocytes1,2. An interaction between the viral envelope gp120 and CD4 protein is required to initiate an infectious cycle3–7. HIV infection in vitro induces syncytium formation by cell-to-cell fusion; this aspect of viral cytopathogenicity is even more dependent on gp120–CD4 interactions4. That gp120 is extremely heavily glycosylated (31–36 N-linked glycans per molecule), suggests involvement of N-linked glycans in the gp120–CD4 interaction8. We therefore investigated the effects of castanospermine, 1-deoxynojirimycin (dNM) and 1-deoxymannojirimycin (dMM), three trimming glycosidase inhibitors which perturb N-linked glycan structure9, on induction of the formation of syncytium between HIV-infected and CD4-expressing cells. The glucosidase inhibitors castanospermine and dNM, but not the mannosidase inhibitor dMM, inhibited syncytium formation and interfered with infectivity. The potential of glucosidase inhibitors as anti-HIV therapeutic agents deserves further investigation, especially because dNM and related compounds show little toxicity in vitro and in vivo9–11.