Cellular effects of ionizing radiation (IR) are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs), single strand breaks (SSBs) and base lesions within a short DNA region of up to 15–20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1) repair resistant, increasing genomic instability (GI) and malignant transformation and (2) can be considered as persistent “danger” signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity). Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.
IntroductionAlthough major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time.MethodsThe statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer.ResultsExpression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis.ConclusionsMajor differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.
In vitro, the antimicrobial agent taurolidine inhibited virtually all of the bacteria tested, including vancomycin-resistant enterococci, oxacillin-resistant staphylococci, and Stenotrophomonas maltophilia, at concentrations between 250 and 2,000 g/ml. Taurolidine was not effective in experimental endocarditis. While it appears unlikely that this antimicrobial would be useful for systemic therapy, its bactericidal activity and the resistance rates found (<10 ؊9 ) are favorable indicators for its possible development for topical use.With the continuing emergence of multiply antibiotic-resistant organisms, the need to develop new therapeutic agents remains evident. Taurolidine [bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)methane], a derivative of the amino acid taurine, is an antimicrobial agent which inhibits and kills a broad range of microorganisms in vitro, albeit at high concentrations (3,4,9,11,13). This compound acts through mechanisms unlike those described for other currently available antimicrobials. Specifically, it is believed that methylol derivatives interact with components of bacterial cell walls resulting in irreparable injury (4). Taurolidine also appears to have immunoregulatory properties, blunting lipopolysaccharide-induced tumor necrosis factor and interleukin-1 release from human peripheral blood mononuclear cells (2) and also reducing adherence of bacteria to human epithelial cells in vitro (5). The compound has been given to humans both intravenously (i.v.) and by peritoneal lavage (1, 12).The purpose of the present study was to examine the in vitro activity of taurolidine against a broad variety of bacterial species, including antibiotic-resistant strains. We also evaluated the activity of taurolidine in vivo in experimental endocarditis using two strains of enterococci, one of which was a vancomycin-resistant strain of Enterococcus faecium.Most of the bacterial strains used in this study were routine isolates collected by our clinical microbiology laboratory during 1997. Additional strains from our collection were included based upon specific resistance traits. Taurolidine was provided by Wallace Laboratories, Cranbury, N.J. Antimicrobial reference standards of ciprofloxacin, imipenem, and cefotaxime were provided by Bayer Corporation, West Haven, Conn.; Merck & Co., Inc., West Point, Pa.; and Hoechst Marion Roussel, Inc., Kansas City, Mo., respectively. Vancomycin was obtained from Eli Lilly & Co., Indianapolis, Ind. MICs were determined by agar dilution (7, 8) on Mueller-Hinton II agar (BBL Microbiology Systems, Cockeysville, Md.) except as noted otherwise. Agar was supplemented with 5% sheep blood for streptococci and diphtheroids. Inocula were ca. 10 4 (10 5 for anaerobes) CFU/spot. Plates were incubated in room air and read at 18 to 20 h, except for lactobacilli, Leuconostoc spp., Pediococcus spp., and pneumococci, which were incubated in 5% CO 2 and examined for growth at 24 h. Anaerobes were incubated for 48 h on brucella agar in an atmosphere produced by Gas-Pak Plus (BBL). Time-...
In the course of clinical studies with the investigational streptogramin antimicrobial dalfopristin-quinupristin, isolates of vancomycin-resistant Enterococcus faecium were referred to our laboratory from across the United States. Seventy-two percent of the strains were of the VanA type, phenotypically and genotypically, while 28% were of the VanB type. High-level resistance to streptomycin or gentamicin was observed in 86 and 81%, respectively, of the VanA strains but in only 69 and 66%, respectively, of the VanB strains. These enterococci were resistant to ampicillin (MIC for 50% of the isolates tested [MIC50] and MIC90, 128 and 256 μg/ml, respectively) and to the other approved agents tested, with the exception of chloramphenicol (MIC90, 8 μg/ml) and novobiocin (MIC90, 1 μg/ml). Considering all of the isolates submitted, dalfopristin-quinupristin inhibited 86.4% of them at concentrations of ≤1 μg/ml and 95.1% of them at ≤2 μg/ml. However, for the data set comprised of only the first isolate submitted for each patient, 94.3% of the strains were inhibited at concentrations of ≤1 μg/ml and 98.9% were inhibited at concentrations of ≤2 μg/ml. Multiple drug resistance was very common among these isolates of vancomycin-resistant E. faecium, while dalfopristin-quinupristin inhibited the majority at concentrations that are likely to be clinically relevant.
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