Myocardial dysfunction in group A streptococcal (GAS) toxic shock syndrome (StrepTSS) is characterized by severe biventricular dilatation and a striking reduction in ventricular performance; however, the mechanisms have not been fully elucidated. We have previously shown that pro-inflammatory cytokines are upregulated in the hearts of experimental animals with GAS bacteremia and that cardiomyocytes themselves as well as macrophages are the principal cytokine sources. Although macrophage-derived cytokines can clearly affect cardiac contractility, we questioned whether soluble cardiomyocyte-derived mediators might in turn affect macrophage function. Thus, we sought evidence of cardiomyocyte-to-macrophage directional cross-talk under resting versus GAS-stimulated conditions, using production of matrix metalloproteinase-9 (MMP-9) as an indicator of such signaling. Our results demonstrate that unstimulated cardiomyocytes produce a soluble inhibitor/s that maintains macrophage functional quiescence. Further, viable GAS induced production of cardiomyocyte-derived stimulator/s that overcomes quiescence and boosts macrophages production of MMP-9 and expression of pro-inflammatory cytokines (IL-1β, IL-6) and cardiodepressant factors (iNOS). Understanding the role of these cardiomyocyte-derived effectors of macrophage function (herein termed "cardiokines") in sepsis-associated cardiomyopathy may suggest new targets for therapeutic intervention.

OBJECTIVE: To compare the prevalence, phenotypes, and genes responsible for erythromycin resistance among Streptococcus pyogenes isolates from Mexico and the USA. METHODS: Eighty-nine invasive and 378 non-invasive isolates from Mexico, plus 148 invasive, 21 non-invasive, and five unclassified isolates from the USA were studied. Susceptibilities to penicillin, erythromycin, clindamycin, ceftriaxone, and vancomycin were evaluated according to Clinical and Laboratory Standards Institute (CLSI) standards. Phenotypes of erythromycin resistance were identified by triple disk test, and screening for mefA, ermTR, and ermB genes was carried out by PCR. RESULTS: All isolates were susceptible to penicillin, ceftriaxone, and vancomycin. Erythromycin resistance was found in 4.9% of Mexican strains and 5.2% of USA strains. Phenotypes in Mexican strains were 95% M and 5% cMLS; in strains from the USA, phenotypes were 33.3% iMLS, 33.3% iMLS-D, and 33.3% M. Erythromycin resistance genes in strains from Mexico were mefA (95%) and ermB (5%); USA strains harbored ermTR (56%), mefA (33%), and none (11%). In Mexico, all erythromycin-resistant strains were non-invasive, whereas 89% of strains from the USA were invasive. CONCLUSIONS: Erythromycin resistance continues to exist at low levels in both Mexico and the USA, although the genetic mechanisms responsible differ between the two nations. These genetic differences may be related to the invasive character of the S. pyogenes isolated.

Life-threatening soft tissue infections caused by Clostridium species have been described in the medical literature for hundreds of years largely because of their fulminant nature, distinctive clinical presentations and complex management issues. The Clostridium species perfringens, septicum and histolyticum are the principal causes of trauma-associated gas gangrene and their incidence increases dramatically in times of war, hurricanes, earthquakes and other mass casualty conditions. Recently, there has also been an increased incidence of spontaneous gas gangrene caused by Clostridium septicum in association with gastrointestinal abnormalities and neutropenia. Similarly, over the last 15 years there has been increased recognition of a toxic shock-like syndrome associated with Clostridium sordellii in individuals skin-popping black tar heroin, in women undergoing childbirth or other gynecologic procedures including medically-induced abortion. Like their cousins Clostridium tetanus and Clostridium botulinum, the pathogenesis of these clostridial infections is largely the consequence of potent exotoxin production. Strategies to inhibit toxin production, neutralize circulating toxins and prevent their interaction with cells of the innate immune response are sorely needed. Recent studies have elucidated novel targets that may hold promise for newer therapeutic modalities.

In 2008, an unusual strain of methicillin-sensitive Staphylococcus aureus (MSSA68111), producing both Panton-Valentine leukocidin (PVL) and toxic shock syndrome toxin-1 (TSST-1), was isolated from a fatal case of necrotizing pneumonia. Because PVL/TSST-1 co-production in S. aureus is rare, we characterized the molecular organization of these toxin genes in strain 68111. MSSA68111 carries the PVL genes within a novel temperate prophage we call ФPVLv68111 that is most similar, though not identical, to phage ФPVL - a phage type that is relatively rare worldwide. The TSST-1 gene (tst) in MSSA68111 is carried on a unique staphylococcal pathogenicity island (SaPI) we call SaPI68111. Features of SaPI68111 suggest it likely arose through multiple major recombination events with other known SaPIs. Both ФPVLv68111 and SaPI68111 are fully mobilizable and therefore transmissible to other strains. Taken together, these findings suggest that hypervirulent S. aureus have the potential to emerge worldwide.

An important stage in tumorigenesis is the ability of precancerous cells to escape natural anticancer signals. Apoptosis can be selectively induced in transformed cells by neighboring normal cells through cytokine and ROS/RNS signaling. The intercellular induction of apoptosis in transformed cells has previously been found to be enhanced after exposure of the normal cells to very low doses of both low- and high-LET ionizing radiation. Low-LET ultrasoft X rays with a range of irradiation masks were used to vary both the dose to the cells and the percentage of normal cells irradiated. The results obtained were compared with those after α-particle irradiation. The intercellular induction of apoptosis in nonirradiated src-transformed 208Fsrc3 cells observed after exposure of normal 208F cells to ultrasoft X rays was similar to that observed for γ rays. Intercellular induction of apoptosis was stimulated by irradiation of greater than 1% of the nontransformed 208F cells and increased with the fraction of cells irradiated. A maximal response was observed when ∼10-12% of the cells were irradiated, which gave a similar response to 100% irradiated cells. Between 1% and 10%, high-LET α particles were more effective than low-LET ultrasoft X rays in stimulating intercellular induction of apoptosis for a given fraction of cells irradiated. Scavenger experiments show that the increase in intercellular induction of apoptosis results from NO(•) and peroxidase signaling mediated by TGF-β. In the absence of radiation, intercellular induction of apoptosis was also stimulated by TGF-β treatment of the nontransformed 208F cells prior to coculture; however, no additional increase in intercellular induction of apoptosis was observed if these cells were also irradiated. These data suggest that the TGF-β-mediated ROS/RNS production reaches a maximum at low doses or fluences of particles, leading to a plateau in radiation-stimulated intercellular induction of apoptosis at higher doses.

Some patients with Group A Streptococcal toxic shock syndrome (StrepTSS) develop a unique form of cardiomyopathy characterized by global hypokinesia and reduced cardiac index. Here we investigated the immune responses of cardiomyocytes to Group A Streptococcus both in vivo and in vitro. Our data demonstrate that cardiomyocyte-derived cytokines are produced following both direct GAS stimulation and after exposure to GAS-activated inflammatory cells. These locally produced, cardiomyocyte-derived cytokines may mediate cardiac contractile dysfunction observed in patients with StrepTSS-associated cardiomyopathy and may hold the key to our ability to attenuate this severe complication.

Clostridial myonecrosis remains an important cause of human morbidity and mortality worldwide. Although traumatic gas gangrene can be readily diagnosed from clinical findings and widely available technologies, spontaneous gas gangrene is more insidious, and gynecologic infections due to Clostridium sordellii progress so rapidly that death often precedes diagnosis. In each case, extensive tissue destruction and the subsequent systemic manifestations are mediated directly and indirectly by potent bacterial exotoxins. The management triumvirate of timely diagnosis, thorough surgical removal of necrotic tissue, and treatment with antibiotics that inhibit toxin synthesis remains the gold standard of care. Yet, despite these measures, mortality remains 30% to 100% and survivors often must cope with life-altering amputations. Recent insights regarding the genetic regulation of toxin production, the molecular mechanisms of toxin-induced host cell dysfunction, and the roles of newly described toxins in pathogenesis suggest that novel prevention, diagnostic, and treatment modalities may be on the horizon for these devastating infections.

Cohesin, a hetero-tetrameric complex of SMC1, SMC3, Rad21 and Scc3, associates with chromatin after mitosis and holds sister chromatids together following DNA replication. Following DNA damage, cohesin accumulates at and promotes the repair of DNA double-strand breaks. In addition, phosphorylation of the SMC1/3 subunits contributes to DNA damage-induced cell cycle checkpoint regulation. The aim of this study was to determine the regulation and consequences of SMC1/3 phosphorylation as part of the cohesin complex. We show here that the ATM-dependent phosphorylation of SMC1 and SMC3 is mediated by H2AX, 53BP1 and MDC1. Depletion of RAD21 abolishes these phosphorylations, indicating that only the fully assembled complex is phosphorylated. Comparison of wild type SMC1 and SMC1S966A in fluorescence recovery after photo-bleaching experiments shows that phosphorylation of SMC1 is required for an increased mobility after DNA damage in G2-phase cells, suggesting that ATM-dependent phosphorylation facilitates mobilization of the cohesin complex after DNA damage.

INTRODUCTION: Severe human infections caused by the Pasteurella species are typically seen following animal bites. P. canis is a species that rarely affects humans and has never been found in systemic infections. Here, we report the first documented case of P. canis bacteremia in an infected human, thought to be caused by a dog lick to an open leg wound.