Molecular epidemiology of vancomycin-resistant Enterococcus faecium in a large urban hospital over a 5-year period

To investigate the dissemination of vancomycin-resistant Enterococcus faecium (VREF) in a 728-bed tertiary-care hospital, all clinical VREF isolates recovered from June 1992 to June 1997 were typed by pulsed-field gel electrophoresis, and the transfer histories of the patients were documented. A total of 413 VREF isolates from urine (52%), wounds (16%), blood (11%), catheter tips (6%), and other sites (15%) were studied. VREF specimens mostly came from patients on wards (66%) but 34% came from patients in an intensive care unit. The number of VREF isolates progressively increased over time, with higher rates of isolation during the winter months and lower rates in the late summer months. Four distinct banding patterns were detected by pulsed-field gel electrophoresis among 316 samples (76%). Strain A (122 samples; 30%) appeared in June 1992 as the first VREF strain and was found until December 1994 throughout the entire hospital. Type B (92 samples; 22%) was initially detected in January 1994 and disappeared in November 1996. Strain C (10 samples; 2%) was limited to late 1996 and early 1997. Strain D (92 samples; 22%) showed two major peaks during March 1996 to August 1996 and January 1997 to February 1997. Unrelated strains (97 samples; 24%) appeared 1 year after the appearance of the first VREF isolate, and the numbers increased slightly over the years. Nosocomial acquisition (i.e., no known detection prior to admission and first isolation from cultures performed with samples retrieved >/=2 days after hospitalization) was found for 316 (91%) of 347 patients. Despite the implementation of Centers for Disease Control and Prevention guidelines, the proportion of related strains and high number of nosocomial cases of infection indicate a high transmission rate inside the hospital. The results imply an urgent need for stringent enforcement of more effective infection control measures.     

Vascular endothelial growth factor receptor signaling is required for cardiac valve formation in zebrafish.

Vascular endothelial growth factor-receptors (VEGF-Rs) are pivotal regulators of vascular development, but a specific role for these receptors in the formation of heart valves has not been identified. We took advantage of small molecule inhibitors of VEGF-R signaling and showed that blocking VEGF-R signaling with receptor selective tyrosine kinase inhibitors, PTK 787 and AAC 787, from 17-21 hr post-fertilization (hpf) in zebrafish embryos resulted in a functional and structural defect in cardiac valve development. Regurgitation of blood between the two chambers of the heart, as well as a loss of cell-restricted expression of the valve differentiation markers notch 1b and bone morphogenetic protein-4 (bmp-4), was readily apparent in treated embryos. In addition, microangiography revealed a loss of a definitive atrioventricular constriction in treated embryos. Taken together, these data demonstrate a novel function for VEGF-Rs in the endocardial endothelium of the developing cardiac valve.     

Opposing effects of tumor necrosis factor-alpha and nerve growth factor upon leukotriene C4 production by human eosinophils triggered with N-formyl-methionyl-leucyl-phenylalanine.

Tumor necrosis factor (TNF) as well as the hematopoietic growth factors interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor affect several eosinophil functions. We previously reported (J. Exp. Med. 1989. 170: 467; 1990. 172: 1577) that the hematopoietic growth factors also potentiate leukotriene C4 (LTC4) formation by eosinophils as well as basophils stimulated with soluble chemotactic peptides such as N-formyl-methionyl-leucyl-phenylalanine (FMLP), but whether TNF also modulates lipid mediator generation in normodense eosinophils triggered with FMLP is unknown. Here we show that a short preincubation (10 min) of human eosinophils purified from healthy donors with low concentrations of TNF (5-150 pM) strongly enhances LTC4 formation in response to FMLP. However, basophil mediator release is not affected by TNF preincubation. Nerve growth factor (NGF), the receptor of which is structurally related to the TNF receptors, tended to suppress lipid mediator synthesis in eosinophils, in contrast to its profound potentiating capacity on basophil mediator release. Thus, the present study demonstrates a first difference in susceptibility of eosinophils and basophils towards cytokines, indicating that TNF and NGF may regulate the relative importance of effector functions of these otherwise closely related cell types.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Evolution of renal replacement therapy in East Germany from 1989 to 1992

Diminished availability of facilities for renal replacementtherapy is known to cause spuriously low acceptance and treatmentrates. In this context the evolution of renal replacement therapyin the former German Democratic Republic is a useful model tostudy and to quantify some of the relevant factors. We performed a survey in all dialysis units for adults in EastGermany (excluding East Berlin) by questionnaire, achievinga response rate of 97%. From December 1989 to December 1992the number of dialysis centres increased from 53 to 96 (+81%),reaching 6.7 centres p.m.p. Of these facilities, 45% were hospitalunits, 29% private units, and 26% dialysis units run by non-profithealth care organizations. The number of dialysis stations forregular dialysis treatment increased from 602 to 1276 (+112%),i.e. 89 stations p.m.p. In parallel, the number of chronic dialysispatients increased from 2127 to 3848 (+81%), i.e. 267 patientsp.m.p. A more detailed survey was carried out in Thüringen andpart of Sachsen, in a region covering 5 million inhabitants.The acceptance rate for chronic dialysis treatment has increasedfrom 49 to 107 patients p.m.p. (+115%). The average age of newpatients increased from 49 to 59 years, the proportion of patientsaged 65 years increased from 16 to 42% and the proportion ofdiabetics from 13 to 35%. Introduction of alternative treatmentmodalities became possible, with 2.3% of the patients receivinghaemofiltrations and 3% CAPD. The proportion of HBs-antigen-positivepatients decreased from 14.2% to 5%. At the end of 1989 in the former GDR (excluding East Berlin),773 patients and, at the end of 1992, 1153 patients were alivewith functioning renal transplants (+49%). The annual rate oftransplantations was 254 in 1989, and 283 in 1992 (+11%), i.e.18 transplantations p.m.p. (including East Berlin). At the end of 1989 2900 patients (193 p.m.p.), and at the endof 1992 5001 patients (347 p.m.p.), werealive on renal replacementtherapy (dialysis or functioning renal transplant) in East Germany,excluding East Berlin; this represents a 72% increase. The figures in East Germany are now almost equivalent to thosein West Germany regarding the number of admissions (incidence),whereas the number of patients on renal replacement therapyis still lower (prevalence).     

Variation of Plasmodium falciparum msp1 block 2 and msp2 allele prevalence and of infection complexity in two neighbouring Senegalese villages with different transmission conditions

To investigate the impact of transmission on the development of immunity to malaria and on parasite diversity, longitudinal surveys have been conducted for several years in Dielmo and Ndiop, 2 neighbouring Senegalese villages with holo- and mesoendemic transmission conditions, respectively. We analysed Plasmodium falciparum msp1 block 2 and msp2 genotypes of isolates collected from 58% of the Dielmo villagers during the same week as those studied recently from Ndiop. Allele frequencies differed in both villages, indicating considerable microgeographical heterogeneity of parasite populations. The complexity of the infections, estimated using individual or combined msp1 and msp2 genotyping, in Dielmo was more than double that in Ndiop and it was age-dependent in Dielmo but not in Ndiop. Thus, this study confirmed the influence of age on the complexity of asymptomatic malaria infections in a holoendemic area. The age distribution of complexity in Dielmo substantiates the interpretation that the number of parasite types per isolate reflects acquired antiparasite immunity. This cross-sectional survey also confirms that the sickle cell trait has no impact on complexity but influences the distribution of P. falciparum genotypes.