@article {21966,
	title = {Are histones real pathogenic agents in sepsis?},
	journal = {NATURE REVIEWS - IMMUNOLOGY},
	year = {2017},
	abstract = {\&nbsp;We read with interest the recent Review article by van der Poll\&nbsp;et al.1(The immunopathology of sepsis and potential therapeutic targets.\&nbsp;Nat. Rev. Immunol.\&nbsp;17, 407{\textendash}420 (2017)).This Review article describes various immunopathological aspects of sepsis and relevant targets as potential therapeutics. Unfortunately, we feel the authors failed to acknowledge highly relevant published data related to the possible pathogenic role of histones in sepsis.In 2009, a paper by Xu\&nbsp;et al.2, published in\&nbsp;Nature Medicine, claimed that the main cause of death in sepsis is the release of highly toxic histones from neutrophils, possibly from those activated to make neutrophil extracellular traps3. Xu and co-workers also showed that the toxicity of histones could be abolished by either heparin, activated protein C or antibodies to histones. However, despite being an important new insight, this study was not cited in the Review by van der Poll and colleagues. Since this study, several other papers have been published showing high levels of circulating histones in many clinical disorders unrelated to sepsis3,4,5,6,7. This has led to the suggestion that histones are not unique inflammation-inducing alarmins (also known as damage-associated molecular patterns (DAMPs)) but are actually markers of cell damage8,9. Notably, in the context of sepsis, highly toxic cationic histones may function not alone but in synergy with oxidants and a range of pro-inflammatory agonists that are also released from activated neutrophils10,11,12,13. Again, none of these publications was acknowledged in the Review by van der Poll and colleagues.We believe this important information on the possible role of histones in sepsis should have been acknowledged in this Review to encourage unbiased reporting and scholarly debate14.\&nbsp;},
	url = {https://www.nature.com/articles/nri.2017.156},
	author = {Ginsburg, I. and Koren, E.}
}
@article {17398,
	title = {Characterization of non-dialyzable constituents from cranberry juice that inhibit adhesion, co-aggregation and biofilm formation by oral bacteria},
	journal = {Food \& Function},
	volume = {8},
	number = {5},
	year = {2017},
	month = {2017},
	pages = {1955-1965},
	abstract = {\&nbsp;An extract prepared from cranberry juice by dialysis known as nondialyzable material (NDM) has been shown previously to possess anti-adhesion activity toward microbial species including oral bacteria, uropathogenic\&nbsp;Escherichia coli\&nbsp;and\&nbsp;Helicobacter pylori. Bioassay-guided fractionation of cranberry NDM was therefore undertaken to identify the anti-adhesive constituents. An aqueous acetone-soluble fraction (NDMac) obtained from Sephadex LH-20 inhibited adhesion-linked activities by oral bacteria, including co-aggregation of oral bacteria\&nbsp;Fusobacterium nucleatum\&nbsp;with\&nbsp;Streptococcus sanguinis\&nbsp;or\&nbsp;Porphyromonas gingivalis, and biofilm formation by\&nbsp;Streptococcus mutans. Analysis of NDMac and subsequent subfractions by MALDI-TOF MS and\&nbsp;1H NMR revealed the presence of A-type proanthocyanidin oligomers (PACs) of 3{\textendash}6 degrees of polymerization composed of (epi)catechin units, with some (epi)gallocatechin and anthocyanin units also present, as well as quercetin derivatives. Subfractions containing putative xyloglucans in addition to the mixed polyphenols also inhibit biofilm formation by\&nbsp;S. mutans\&nbsp;(MIC = 125{\textendash}250 μg mL-1). These studies suggest that the anti-adhesion activities of cranberry NDM on oral bacteria may arise from a combination of mixed polyphenol and non-polyphenol constituents.\&nbsp;},
	url = {http://pubs.rsc.org/en/content/articlepdf/2017/fo/c7fo00109f},
	author = {Neto, C. C. and Penndorf, K.A. and Feldman, M. and Meron-Sudai, S. and Zakay-Rones, Z. and Steinberg, D. and Fridman, M. and Kashman, Y. and Ginsburg, I. and Ofek, I. and Weiss, E. I.}
}
@article {20830,
	title = {From amino acids polymers, antimicrobial peptides, and histones, to their possible role in the pathogenesis of septic shock: a historical perspective},
	journal = {Journal of Inflammation Research},
	volume = {10},
	year = {2017},
	pages = {7-15},
	abstract = {This paper describes the evolution of our understanding of the biological role played by synthetic and natural antimicrobial cationic peptides and by the highly basic nuclear histones as modulators of infection, postinfectious sequelae, trauma, and coagulation phenomena. The authors discuss the effects of the synthetic polymers of basic poly α amino acids, poly l-lysine, and poly l-arginine on blood coagulation, fibrinolysis, bacterial killing, and blood vessels; the properties of natural and synthetic antimicrobial cationic peptides as potential replacements or adjuncts to antibiotics; polycations as opsonizing agents promoting endocytosis/phagocytosis; polycations and muramidases as activators of autolytic wall enzymes in bacteria, causing bacteriolysis and tissue damage; and polycations and nuclear histones as potential virulence factors and as markers of sepsis, septic shock, disseminated intravasclar coagulopathy, acute lung injury, pancreatitis, trauma, and other additional clinical disorders},
	url = {https://www.dovepress.com/from-amino-acids-polymers-antimicrobial-peptides-and-histones-to-their-peer-reviewed-article-JIR},
	author = {Ginsburg, I. and Van Heerden, V. and Koren, E.}
}
@article {20829,
	title = {Is Histone a Solitary Vile Sepsis-Inducing Agent or Just \&quot;a Member of the Gang\&quot;?},
	journal = {Journal of Infectious Diseases and Therapy},
	volume = {5},
	number = {4},
	year = {2017},
	abstract = {\&nbsp;In this communication we argue that it is improbable that the main cause of death in sepsis is that, upon releaseof extracellular traps from neutrophils adhering to endothelial cells, highly cationic toxic histones uniquely causeendothelial dysregulation, organ failure and death. Activation of neutrophils is always accompanied by a plethora ofpro-inflammatory agents, which may act in synergy with histones to injure cells. Furthermore, many recent articleshave shown a steep rise of circulating histones in many clinical disorders unrelated to sepsis. We argue thereforethat histones do not act as unique alarmins with an outsized role, but are probably another marker of cell damage.\&nbsp;},
	url = {https://www.omicsonline.org/open-access/is-histone-a-solitary-vile-sepsisinducing-agent-or-just-a-member-of-thegang-2332-0877-1000329.php?aid=91999},
	author = {Ginsburg, I. and Koren, E. and Trahtemberg, U. and Van Heerden, V.}
}
@booklet {21090,
	title = {Sepsis Pathogenicity and Histones: Are we \&ldquo;Re-discovering the Wheel\&rdquo;?},
	number = {Sepsis},
	year = {2017},
	abstract = {It is alarming that today clinicians are still helpless trying to cope with life-threatening sequelae of severe microbial infections, which very often terminates in sepsis, septic shock and death. According to CDC (The Centers for Disease Control and Prevention) today the annual incidence of sepsis in the USA affects as many as 7,50,000 hospitalized patients and mortality rates are about 40\% [1]. As of today, all the clinical trials of sepsis, which had tried the efficacy of only a single antagonist at a time, had failed to protect against septic shock, a disorder obviously caused by multi-factorial processes. Even the {\textquotedblleft}hope of sepsis{\textquotedblleft}, activated protein C (APC), has recently been discontinued. Today, no effective treatment for sepsis is available and the morality rates are climbing steadily also because of the rapid acquisition of antibiotic resistance.},
	url = {http://smgebooks.com/sepsis/chapters/SEP-17-13.pdf},
	author = {Ginsburg, I. and Koren, E. and Varani, J. and Kohen, R.}
}
@article {17404,
	title = {Serum histones as biomarkers of the severity of heatstroke in dogs},
	journal = {Cell Stress \& Chaperones},
	volume = {Epub ahead of print},
	year = {2017},
	month = {2017},
	abstract = {Heatstroke is associated with systemic inflammatory response syndrome, leading to multiple organ dysfunction and death. Currently, there is no specific treatment decreasing hyperthermia-induced inflammatory/hemostatic derangements. Emerging studies indicate that histones leaking from damaged cells into the extracellular space are toxic, pro-inflammatory, and pro-thrombotic. We therefore hypothesize that serum histones (sHs) are elevated during heatstroke and are associated with the severity of the disease. Sixteen dogs with heatstroke and seven healthy controls were included in the study. Median serum histones (sHs) upon admission in dogs with heatstroke were significantly higher (P\&nbsp;=\&nbsp;0.043) compared to that in seven controls (13.2 vs. 7.3\&nbsp;ng/mL, respectively). sHs level was significantly higher among non-survivors and among dogs with severe hemostatic derangement (P\&nbsp;=\&nbsp;0.049, median 21.4\&nbsp;ng/mL vs. median 8.16\&nbsp;ng/mL and P\&nbsp;=\&nbsp;0.038, 19.0 vs. 7.0\&nbsp;ng/mL, respectively). There were significant positive correlation between sHs and urea (r\&nbsp;=\&nbsp;0.8, P\&nbsp;=\&nbsp;0.02); total CO2 (r\&nbsp;=\&nbsp;0.661, P\&nbsp;=\&nbsp;0.05); CK (r\&nbsp;=\&nbsp;0.678, P\&nbsp;=\&nbsp;0.04); and prothrombin time (PT) 12\&nbsp;h post presentation (r\&nbsp;=\&nbsp;0.888, P\&nbsp;=\&nbsp;0.04). The significant positive correlation between sHs and other heatstroke severity biomarkers, and significant increase among severely affected dogs, implies its role in inflammation/oxidation/coagulation during heatstroke. sHs, unlike other prognostic and severity biomarkers in heatstroke, can be pharmacologically manipulated, offering a potential therapeutic target.},
	url = {https://www.ncbi.nlm.nih.gov/pubmed/28643239},
	author = {Yaron Bruchim and Isaac Ginsburg and Segev, Gilad and Ahmad Mreisat and Yochai Avital and Itamar Aroch and Michal Horowitz}
}
@article {21091,
	title = {Tissue damage in post infectious sequelae is caused by a synergism between microbial and neutrophils-derived agonists: a concern for a disregard for already published data},
	journal = {Journal of Emerging and Rare Diseases},
	volume = {1},
	number = {1},
	year = {2017},
	pages = {1-3},
	abstract = {Post infectious sequelae such as sepsis and septic shock are poorly understood and annually take the lives of millions over the world. Severe microbial infections caused by Gram Positive and Gram Negative bacteria and by fungi are the main causes, which are aggravated by the rapid development of antibiotic resistance. It is unfortunate that today all the clinical trials of sepsis which tested the efficacy of single antagonists failed. Sepsis was recently redefined as a synergistic multifactorial episode where no unique alarmin had been identified, which if inhibited could control the deleterious biochemical and immune immunological events characteristic of sepsis. An apparent {\textquotedblleft}breakthrough {\textquotedblleft}in our understanding of sepsis pathogenicity was published in 2009 in Nature Medicine arguing that the main cause of mortality in sepsis is the release from neutrophils (PMNs) nets of highly toxic nuclear histone. This caused endothelial cell dysregulation leading to organ failure. However, this concept downplays the concept that concomitantly with the activation of PMNs, a plethora of additional proinflammatory agents is also released. These can act in synergy with histone to injure cells. Furthermore, since many additional clinical disorders not related to sepsis also reported high levels of circulating histones, this toxic agent may be considered just another marker of cell damage. The failure to treat sepsis by the administration of only single antagonists should be replaced by cocktails of appropriate anti inflammatory agents.},
	url = {https://www.boffinaccess.com/open-access-journals/journal-of-emerging-and-rare-diseases/jer-1-101.pdf},
	author = {Ginsburg, I. and Koren, E. and Van Heerden, V.}
}
