Mediterranean spotted fever caused by Rickettsia conorii is a potentially lethal disease characterized by vascular inflammation affecting multiple organs. Studies of R. conorii so far have focused on ...activation of inflammatory cells and their release of inflammatory cytokines, but complement activation has not been investigated in R. conorii-infected patients. Here, we performed a comprehensive analysis of complement activation markers and the soluble cross-talking co-receptor CD14 (sCD14) in plasma from R. conorii-infected patients. The clinical data were supplemented with ex vivo experiments where the cytokine response was characterized in human whole blood stimulated with R. conorii. Complement activation markers at the level of C3 (C3bc, C3bBbP) and terminal pathway activation (sC5b-9), as well as sCD14, were markedly elevated (p <0.01 for all), and closely correlated (p <0.05 for all), in patients at admission compared with healthy matched controls. All tested markers were significantly reduced to baseline values at time of follow up. Rickettsia conorii incubated in human whole blood was shown to trigger complement activation accompanied by release of the inflammatory cytokines interleukin-1β (IL-1β), IL-6, IL-8 and tumour necrosis factor. Whereas inhibition of either C3 or CD14 had only a minor effect on released cytokines, combined inhibition of C3 and CD14 resulted in significant reduction, virtually to baseline levels, of the four cytokines (p <0.05 for all). Our data show that complement is markedly activated upon R. conorii infection and complement activation is, together with CD14, responsible for a major part of the cytokine response induced by R. conorii in human whole blood.
The increasing incidence of Clostridium difficile infections (CDI) in healthcare settings in Europe since 2003 has affected both patients and healthcare systems. The implementation of effective CDI ...surveillance is key to enable monitoring of the occurrence and spread of C. difficile in healthcare and the timely detection of outbreaks.
The aim of this review is to provide a summary of key components of effective CDI surveillance and to provide some practical recommendations. We also summarize the recent and current national CDI surveillance activities, to illustrate strengths and weaknesses of CDI surveillance in Europe.
For the definition of key components of CDI surveillance, we consulted the current European Society of Clinical Microbiology and Infectious Diseases (ESCMID) CDI-related guidance documents and the European Centre for Disease Prevention and Control (ECDC) protocol for CDI surveillance in acute care hospitals. To summarize the recent and current national CDI surveillance activities, we discussed international multicentre CDI surveillance studies performed in 2005–13. In 2017, we also performed a new survey of existing CDI surveillance systems in 33 European countries.
Key components for CDI surveillance are appropriate case definitions of CDI, standardized CDI diagnostics, agreement on CDI case origin definition, and the presentation of CDI rates with well-defined numerators and denominators. Incorporation of microbiological data is required to provide information on prevailing PCR ribotypes and antimicrobial susceptibility to first-line CDI treatment drugs. In 2017, 20 European countries had a national CDI surveillance system and 21 countries participated in ECDC-coordinated CDI surveillance. Since 2014, the number of centres with capacity for C. difficile typing has increased to 35 reference or central laboratories in 26 European countries.
Incidence rates of CDI, obtained from a standardized CDI surveillance system, can be used as an important quality indicator of healthcare at hospital as well as country level.
Display omitted
Quantitative and qualitative changes in epidermal polyamine levels and DNA synthesis (specific activity and labeling index) after a single topical application of 12-O-tetradecanoylphorbol-13-acetate ...(TPA), mezerein (MEZ), or ethylphenylpropiolate (EPP) in acetone were studied concomitantly in the same epidermal cell population from each treated mouse. The doses tested were 17 nmol of TPA; 1.7, 8.5, and 17 nmol of MEZ; and 20 mumol of EPP. With relatively small variations in time patterns, both the tumor promoter TPA and the mitogens MEZ and EPP caused similar sequential changes: initial inhibition of DNA synthesis; induction of L-ornithine decarboxylase activity; and subsequent peaks of putrescine levels preceding peaks in the rate of DNA synthesis. A remarkably good correlation between the molar ratio of spermidine/spermine and the increase in DNA synthesis was seen after all three of the compounds. However, in the initial period with inhibited DNA synthesis, a negative correlation between spermidine/spermine and DNA synthesis was observed after all of the treatments. TPA and MEZ induced pronounced biphasic increases in DNA synthesis, accumulation of putrescine, and the spermidine/spermine ratio, whereas EPP induced single-peaked increases in the same variables. The fluctuations in polyamine levels and DNA synthesis were associated with cohorts of partly synchronized cells passing the cell cycle multiple turns. Thus, the induction of L-ornithine decarboxylase and the polyamines does not seem to be specific for tumor promotion but merely seems to be associated with the cell kinetic events during stimulated cell proliferation. It is suggested that quantitative aspects of hyperproliferation may be essential for tumor promotion.
A single application of 17 nmol of 12-O-tetradecanoyl phorbol-13-acetate (TPA) to mouse skin caused a marked (200-to 400-fold) induction of ornithine decarboxylase (EC 4.1.1.17, L-ornithine ...carboxy-lyase) activity in mouse epidermal and epidermal-dermal preparations. No change in the basal level of 3′:5′-cyclic AMP occurred in epidermal-dermal preparations within 30 min of TPA application. Intraperitoneal injection of the β -agonist isoproterenol resulted in a dose-dependent accumulation of 3′:5′-cyclic AMP 10 min after injection, but caused no induction of ornithine decarboxylase. When isoproterenol was injected 10 min prior to an application of either 1.7 or 17 nmol of TPA, the magnitude of the ornithine decarboxylase induction was the same as induction with TPA alone. Topical application of 17 nmol of TPA caused no increase in the level of 3′:5′-cyclic GMP present in the mouse epidermaldermal preparations 2-20 min after application. Intraperitoneal injection of 1.75 μ mol of dibutyryl 3′:5′-cyclic GMP caused a 6-fold increase in the level of cyclic GMP and/or butyryl derivatives of cyclic GMP in epidermal-dermal preparations within 5 min of injection, and the level remained elevated for at least 20-30 min. This dose of dibutyryl 3′:5′-cyclic GMP was incapable of inducing ornithine decarboxylase. Injection of dibutyryl 3′:5′-cyclic GMP 5 min before application of 1.7 nmol of TPA or 30 min before application of 17 nmol of TPA did not alter the magnitude of the ornithine decarboxylase induction produced by TPA alone. These results suggest that early increases in the total intracellular levels of either 3′:5′-cyclic AMP or 3′:5′-cyclic GMP are not part of the mechanism by which TPA induces ornithine decarboxylase in the epidermis.
Mouse skin has a long history as a useful model for the study of the mechanism of carcinogenesis (6). In particular, the availability of specific diterpene esters has made possible rapid progress in ...understanding the mechanism of tumor formation (4,6,8,19,36,41), although certain details may be unique to promotion by phorbol esters. Evidence is compatible with an essential role for elevated levels of polyamines in tumor promotion, but other components of phorbol ester action on mouse skin are also essential (27,40,54). These may include the production of dark cells (22), inhibition of maturation (2,19,41), and the elimination of metabolic cooperation (12,57). Factors modifying biochemical processes that are essential to tumor formation produce a parallel effect on tumor formation. Some of these inhibitors act synergistically to inhibit tumor formation (50,55), and knowledge of their action may lead to practical application for the prevention of human cancer.
The activity levels of L-ornithine carboxy-lyase (ODC) (E.C. 4.1.1.17) and S-adenosyl-L-methionine carboxy-lyase (SAM-D) (E.C.4.1.1.50) were determined in individual papillomas induced in mouse skin ...by a two-stage technique, and in normal mouse epidermis. Cycloheximide treatment abolished both enzyme activities. In normal epidermis the ODC activity was barely detectable, whereas the tumors exhibited high levels of ODC. Levels of SAM-D activity above those of normal epidermis were detected in some papillomas, but in contrast to ODC the SAM-D activity levels were not consistently increased in skin tumors. By pooling a great number of papillomas, the variations in ODC and SAM-D activities between different papillomas could be minimized so that reliable measurements of the biological half-lives of ODC and SAM-D in the tumors were obtained using cycloheximide treatment. The half-life of SAM-D in squamous papillomas was 45 min, almost identical to the 41 min half-life of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced level of this enzyme in normal mouse epidermis. In contrast, the ODC activity of the mouse skin papillomas declined at a rate similar to that in TPA-treated epidermis for only the first 15-20 min after cycloheximide injection. Thereafter, at time points when protein synthesis was approximately 90% inhibited, the ODC activity reverted to high levels. These results show that the high level of ODC activity in squamous papillomas is stabilized. This observation is compatible with the hypothesis that the control mechanism of the ODC activity level in these tumors is severely deranged. This change in polyamine turnover pattern may be related to altered differentiation of the epidermal cells, which constitute the main bulk of cells in these tumors.
PDF
