Publications

2004
  PADMA-28, a Tibetan herbal preparation is an inhibitor of inflammatory cytokine production
Barak V, Kalickman I, Halperin T, Birkenfeld S, Ginsburg I.   PADMA-28, a Tibetan herbal preparation is an inhibitor of inflammatory cytokine production. European Cytokine Network. 2004;15 (3) :203-209.Abstract
BACKGROUND: Previous studies have shown that PADMA-28, a multicomponent, traditional Tibetan herbal plant preparation possesses a variety of beneficial effects on several experimental models of inflammatory and immune processes, including autoimmune diabetes and autoimmune encephalomyelitis. In humans, PADMA-28 attenuated the symptoms associated with intermittent claudications in atherosclerotic patients. OBJECTIVE: To assess the effect of PADMA 28 on the immune system, e.g. cytokine (interleukins) production. DESIGN: Cytokine production by human blood monocytes (derived from 12 healthy donors) stimulated in vitro, either by endotoxin (LPS) from Salmonella typhi or by lipoteichoic acid (LTA) from group A Streptococci was modulated by PADMA-28. RESULTS: The present study showed that an aqueous extract of PADMA-28 strongly decreased the production of the inflammatory cytokines IL-1beta, IL-6, IL-8 and TNF-alpha, and more moderately, also decreased the anti-inflammatory cytokine IL-10 induced by LPS. However, the LTA - induced IL-10 production was [not significantly] increased by the low dose PADMA-28, while not effected at all by the higher dose of PADMA-28. CONCLUSIONS: The data from these finding suggest a possible clinical efficacy of PADMA-28 either in autoimmune and in inflammatory conditions or in post-inflammatory sequelae, as previously shown in in vivo and human studies, probably by decreasing inflammatory cytokines.
2002
Cationic polyelectrolytes from leukocytes might kill bacteria by activating their autolytic systems: Enigmatically, the relevance of this phenomenon to post-infectious sequelae is disregarded
Ginsburg I. Cationic polyelectrolytes from leukocytes might kill bacteria by activating their autolytic systems: Enigmatically, the relevance of this phenomenon to post-infectious sequelae is disregarded. Intensive Care Medicine. 2002;28 (8) :1188.Abstract
Linear polymers of lysine and arginine, phagocyte-derived lysozyme, PLA, elas- tase, cathepsin G, myeloperoxidases, nu- clear histone and bacterial/permeability-en- hancing peptide (BPI) and defensins all possess bactericidal activities [1, 2, 3, 4, 5, 6]. The highly cationic BPI and defensins might kill Gram-negatives primarily by de- polarizing their outer membrane to en- hance its permeability [3]. However, it had also been proposed that many of these polycations might also function as “Trojan Horses” to disrupt the intracellular regula- tion of the autolytic wall enzyme systems (muramidases).This can lead to cleavage of the peptidoglycan, to bacteriolysis, and to cell death [4, 5, 6].The highly cationic, ly- sozyme, PLA2, and elastase probably do not function solely as enzymes, but rather as highly cationic agents. The bactericidal and bacteriolytic effects of polycations might therefore mimic the bacteriolytic ef- fects caused by beta-lactam antibiotics. Sulfated compounds (heparin, dextran sul- fate, polyaenthole sulfonate) very efficient- CORRESPONDENCE ly inhibited the activation of bacterial au- tolysis induced either by cationic agents or by beta-lactam antibiotics [4, 5, 6, 7]. Therefore, it is highly likely that polycat- ions of plasma and leukocyte origins might be actively involved in the pathophysiolo- gy of post-infectious sequelae by their ca- pacity to induce a massive release of high- ly phlogistic lipoteichoic acid [7] endotox- in, lipoprotein, and peptidoglycan [8]. Combinations among these agents might act on mononuclear cells to generate reactive oxygen species, NO, NOO-, hy- drolases, and also to activate the coagula- tion, complement, and cytokine cascades, all involved in septic shock. Based on the above arguments, it is tempting to specu- late that the failure to depress early bacteri- olysis in the bloodstream might be the main cause for the inability to cope with the multiple synergistic interactions lead- ing to post-infectious sequelae [9]. The clinical use of polyanions when combined with mutli drug strategies might therefore be recommended as potent anti-bacteriolyt- ic and anti-inflammatory agents [10]. It is enigmatic why publications that have pro- posed the role of polycations in bacterioly- sis and the possibility to inhibit its unto- ward effects by polyanions, findings so rel- evant to the patholysiology of post-infec- tious sequelae, are consistently disregarded [11] either in basic science publications on the bactericidal effects of polycations or in the clinical literature dealing with post-in- fectious sequelae.
Hemolysis of human erythrocytes by hypochlorous acid is modulated by amino acids, antioxidants, oxidants, membrane-perforating agents and by divalent metals
Ginsburg I, Sadovnik M, Yedgar S, Kohen R, Hrbac J. Hemolysis of human erythrocytes by hypochlorous acid is modulated by amino acids, antioxidants, oxidants, membrane-perforating agents and by divalent metals. Free Radical Research. 2002;36 (6) :607-619.Abstract
The optimal conditions under which hypochlorous acid (NaOCl) either hemolyzes human RBC or kills monkey kidney epithelial cells (BGM) in culture had been investigated. While in Hank's balanced salt solution (HBSS), micromolar amounts of NaOCl caused full hemolysis and also killed BGM cells, in D-MEM or RPMI media rich in amino acids, 25-40 mM of hypochlorite were needed to induce cell injury. Cells exposed to high amounts of NaOCl became highly refractory to strong detergents. Hemolysis by NaOCl was strongly inhibited by a large variety of antioxidants. RBC treated by subtoxic concentrations either of peroxide, peroxyl radical, NO, cholesterol, PLA2, PLC as well as by N2, argon or by mixture of CO2 (10%) and O2 (90%) became much more susceptible to lysis by NaOCl. On the other hand, while RBC treated by Fe2+, Co2+, and V2+ and to a lesser extent with Cu2+ became highly resistant to NaOCl hemolysis presumably due to NaOCl decomposition, no such effect was found either with Co2+ or by Mn2+. RBC treated by azide to destroy catalase and then incubated with peroxide and with NaOCl failed to undergo hemolysis due to the ability of peroxide to decompose NaOCl. The inhibitory effects of the divalent metals on NaOCl-induced hemolysis were also substantiated by measuring the decrease in pH and by cyclic voltammetry. The findings that like peroxide, NaOCl also synergizes with membrane-perforating agents and with a protease to kill epithelial cells further implicate such "cocktails" in cell injury in inflammatory conditions. Taken together, because of the capacity of many agents to scavenge NaOCl, tissue damage by NaOCl-generated neutrophils can take place primarily if activated neutrophils closely adhere to target cells to avoid the scavenging effects of amino acids and of antioxidants. Therefore, the significance of the data which had tested the cytotoxic effects of NaOCl using cells suspended only in salt solutions, should be reconsidered.
Role of lipoteichoic acid in infection and inflammation
Ginsburg I. Role of lipoteichoic acid in infection and inflammation. The Lancet Infectious Diseases. 2002;2 (3) :171-179.Abstract
Lipoteichoic acid (LTA) is a surface-associated adhesion amphiphile from Gram-positive bacteria and regulator of autolytic wall enzymes (muramidases). It is released from the bacterial cells mainly after bacteriolysis induced by lysozyme, cationic peptides from leucocytes, or beta-lactam antibiotics. It binds to target cells either non-specifically, to membrane phospholipids, or specifically, to CD14 and to Toll-like receptors. LTA bound to targets can interact with circulating antibodies and activate the complement cascade to induce a passive immune kill phenomenon. It also triggers the release from neutrophils and macrophages of reactive oxygen and nitrogen species, acid hydrolases, highly cationic proteinases, bactericidal cationic peptides, growth factors, and cytotoxic cytokines, which may act in synergy to amplify cell damage. Thus, LTA shares with endotoxin (lipopolysaccharide) many of its pathogenetic properties. In animal studies, LTA has induced arthritis, nephritis, uveitis, encephalomyelitis, meningeal inflammation, and periodontal lesions, and also triggered cascades resulting in septic shock and multiorgan failure. Binding of LTA to targets can be inhibited by antibodies, phospholipids, and specific antibodies to CD14 and Toll, and in vitro its release can be inhibited by non-bacteriolytic antibiotics and by polysulphates such as heparin, which probably interfere with the activation of autolysis. From all this evidence, LTA can be considered a virulence factor that has an important role in infections and in postinfectious sequelae caused by Gram-positive bacteria. The future development of effective antibacteriolitic drugs and multidrug strategies to attenuate LTA-induced secretion of proinflammatory agonists is of great importance to combat septic shock and multiorgan failure caused by Gram-positive bacteria.
The role of bacteriolysis in the pathophysiology of inflammation, infection and post-infectious sequelae
Ginsburg I. The role of bacteriolysis in the pathophysiology of inflammation, infection and post-infectious sequelae. APMIS. 2002;110 (11) :753-770.Abstract
The literature dealing with the biochemical basis of bacteriolysis and its role in inflammation, infection and in post-infectious sequelae is reviewed and discussed. Bacteriolysis is an event that may occur when normal microbial multiplication is altered due to an uncontrolled activation of a series of autolytic cell-wall breaking enzymes (muramidases). While a low-level bacteriolysis sometimes occurs physiologically, due to "mistakes" in cell separation, a pronounced cell wall breakdown may occur following bacteriolysis induced either by beta-lactam antibiotics or by a large variety of bacteriolysis-inducing cationic peptides. These include spermine, spermidine, bactericidal peptides defensins, bacterial permeability increasing peptides from neutrophils, cationic proteins from eosinophils, lysozyme, myeloperoxidase, lactoferrin, the highly cationic proteinases elastase and cathepsins, PLA2, and certain synthetic polyamino acids. The cationic agents probably function by deregulating lipoteichoic acid (LTA) in Gram-positive bacteria and phospholipids in Gram-negative bacteria, the presumed regulators of the autolytic enzyme systems (muramidases). When bacteriolysis occurs in vivo, cell-wall- and -membrane-associated lipopolysaccharide (LPS (endotoxin)), lipoteichoic acid (LTA) and peptidoglycan (PPG), are released. These highly phlogistic agents can act on macrophages, either individually or in synergy, to induce the generation and release of reactive oxygen and nitrogen species, cytotoxic cytokines, hydrolases, proteinases, and also to activate the coagulation and complement cascades. All these agents and processes are involved in the pathophysiology of septic shock and multiple organ failure resulting from severe microbial infections. Bacteriolysis induced in in vitro models, either by polycations or by beta-lactams, could be effectively inhibited by sulfated polysaccharides, by D-amino acids as well as by certain anti-bacteriolytic antibiotics. However, within phagocytic cells in inflammatory sites, bacteriolysis tends to be strongly inhibited presumably due to the inactivation by oxidants and proteinases of the bacterial muramidases. This might results in a long persistence of non-biodegradable cell-wall components causing granulomatous inflammation. However, persistence of microbial cell walls in vivo may also boost innate immunity against infections and against tumor-cell proliferation. Therapeutic strategies to cope with the deleterious effects of bacteriolysis in vivo include combinations of autolysin inhibitors with combinations of certain anti-inflammatory agents. These might inhibit the synergistic tissue- and- organ-damaging "cross talks" which lead to septic shock and to additional post-infectious sequelae.
2001
A psychometric study of patients with nail dystrophies
Alam M, Moossavi M, Ginsburg I, Scher RK. A psychometric study of patients with nail dystrophies. Journal of the American Academy of Dermatology. 2001;45 (6) :851-856.Abstract
BACKGROUND: Survey studies suggest that patients with various dermatologic conditions experience concomitant psychologic distress. OBJECTIVE: The purpose of this study was to determine which types of psychologic distress may be correlated with dystrophic disease of the nail in nonpsychiatric patients. METHODS: Fifty-seven adult subjects presenting for treatment of nail dystrophies completed a survey instrument, which included 5 psychometric measures. RESULTS: On average, patients rated the severity of their nail dystrophy and functional deficit higher (7.40/10 and 6.00, respectively) than investigators (6.15 and 3.75, respectively). Compared with age- and sex-matched nonpsychiatric patients, subjects in the study were moderately more anxious and minimally to mildly more depressed. Subjects had moderately depressed total self-concept, but their body image was approximately normal. Overall, subjects exhibited markedly more severe psychologic symptoms (84th percentile) than the normal sample, with the scores on the psychoticism, obsessive-compulsive, and paranoid ideation subscales being the most elevated. CONCLUSION: The subjects with nail dystrophy had markedly exacerbated psychologic symptoms compared with age- and sex-matched nonpsychiatric patients.
Disregard of Pre-Medline Literature and the Future of Honest Science
Ginsburg I. Disregard of Pre-Medline Literature and the Future of Honest Science. ASM News- Letters to the editor. 2001;67 (7).Abstract
As we enter the third millennium, we witness the rapid continuation of the unprecedented explosion of scientific information. Today, we are fortunate to have access to Medline and to electronic journals covering the mammoth fields of biological sciences. It presumably assures us that we can no longer miss important relevant recent publications crucial to the continuation of our original line of research. Unfortunately, we witness today a dangerous trend that despite having access to Index Medicus and additional abstracting systems covering the literature prior to 1960, younger investigators tend to refrain from citing "older" publications, assuming that they are already passe. Obviously, it necessitates spending time in libraries. But who, in these "modern" computerized days, has time to wait? Over the last few years, I tried to find out what was behind this behavior. I took the liberty of writing to authors who published papers in my own field of research and who failed to cite crucial key publications from the pre-Medline era, without which I believe they cannot even start to understand the evolution of their own current research. The following are only several of the responses I received: "I do not read the Journals which you claimed had included papers relevant for my research paper." "I was unaware of the publications you proposed, but will be happy to read them if you can send them to me. I might consider citing them in my future review on the subject." "Restrictions over the numbers of reference permissible prevented me from citing the proposed articles." "The library at my university gives me a hard time trying to retrieve older literature." "The focus of my article was to narrow down only on the most relevant current information available on the subject." "Reviews covering the topic of my current investigations had recently been published." (However, no such review was cited by the author.) "I do not have the time to comment on your thoughts in a scholarly fashion. However, bear in mind that the papers you had listed have not gone completely unnoticed." (Really?) "You will recognize that it is not easy to find papers from several years unless they are cited by others, as there is literally too much information about" "As a newcomer to this field of research, I neglected to read relatively old articles and I restricted myself to critically report the most common views on the subject. Besides, I was unable to receive the older articles you mentioned, because they are unavailable in the library of our relatively new university." "I had, as you guessed, not seen your work. I am unfamiliar with most of the journals in which you publish—-and also I am not an immunologist." The following is also a reminder how certain line of research might become extinct. A review on the role of proteinases in tissue damage concluded that proteinases might also synergize with oxidants and with additional pro-inflammatory agents. Yet, publications since 1960 which had described this phenomenon had not been included either in this particular paper or in any of the papers on the subject. A main line of research had proposed that cationic proteins from leukocytes might kill bacteria by altering the permeability of their membranes. Yet, none of a very large series of investigations by others since the early 1970s, which had proposed an alternative possible mechanism suggesting that cationic proteins might kill microorganisms also by their ability to induce bacteriolysis, are ever cited anywhere. Because of a change in nomenclature, pioneering investigations from 1951-1957, which had described the properties and mechanisms of action of bacterial cell-sensitizing agents (HF), had literally been eliminated because today this factor is called lipoteichoic acid (LTA). One simple sentence, and including proper citations stressing that LTA was previously called HF, might have sufficed to prevent unnecessary repetitions of the same experiments. The following proposals might be adopted by editorial boards of journals to assure and also fight against the "disregard syndrome." (i) Every paper should include an introductory historical coverage of the "pioneering" investigations on which the current research is based. (ii) Emeriti professors, who might have read "older investigations" in a particular field of research, be nominated as referees. This might also stimulate emeriti professors to be reinvolved in the activities of the scientific community. (iii) A "Letters to the Editor" section in every Journal be established where authors can alert their readers to the existence of "old" literature on the subject. (iv) To combat the unacceptable attitude where publications which do not "fit" current thoughts and ideas are simply concealed from the modern reader. This is unethical and also self-defeating. Only a strong stand by Editorial Boards against the "disregard syndrome" might help to advance honest science.
The Disregard Syndrome: A Menace to Honest Science?
Ginsburg I. The Disregard Syndrome: A Menace to Honest Science?. The Scientist. 2001;15 (24) :51.Abstract
We are witnessing the continuation of an accelerated, unprecedented explosion of scientific information that might make the life of a serious investigator unbearably complicated. Unlike our pioneering investigators, however, we are fortunate to have access to modern information-retrieving pools such as Medline, Biological Abstracts, and more recently selected electronic journals. These allow us, at the press of a key, to choose desired scientific citations. A search for articles in the medical
HYPOTHESIS: Is a Failure to Prevent Bacteriolysis and the Synergy Among Microbial and Host-Derived Pro-Inflammatory Agonists the Main Contributory Factors to the Pathogenesis of Post-Infectious Sequelae?
Ginsburg I. HYPOTHESIS: Is a Failure to Prevent Bacteriolysis and the Synergy Among Microbial and Host-Derived Pro-Inflammatory Agonists the Main Contributory Factors to the Pathogenesis of Post-Infectious Sequelae?. Inflammation. 2001;25 (1) :1-6.Abstract
INTRODUCTION Why Have Clinical Trials of Sepsis Been Unsuccessful? It is disconcerting that entering the third millennium, severe microbial infections and their sequelae e.g., sep- sis, septic shock, ARDS, “flesh-eating syndromes,” still claim the lives of numerous patients annually. Further- more, it is of great interest that while immunomodu- lating agents have proved beneficial in the treatment of inflammatory conditions such as rheumatoid arthri- tis, a large series of clinical trials which have been con- ducted in the last decade and which have mainly tested only single immunomodulating agents as therapies for septic shock, have been mostly unsuccessful. In 1996, Verhoef et al. (1) have stated that reviewing the liter- ature on sepsis therapies “the area of immunomodula- tion has now become an area of more realism and the results of early trials have forced investigators to go back to the drawing board to re-investigate the whole con- cept of immunotherapy and immunoprophylaxis. In a more recent Point of View in Critical Care Medicine, entitled “Sepsis research: We must change course,” Dr. Nasraway has hit the nail on its head (2). Reviewing the disappointing results of no less than 29 prospec- tive controlled studies of human sepsis performed in the last decade, he has questioned whether “it is rational to attempt to alter the inflammatory responses by admin- istering a single immunomodulating agent while simul- taneously failing to control for the many interventions that also alter cytokine expression?” He has also raised serious doubts about the morality of any future trials of sepsis if conducted in the present manner. Baue (3), Opal and Yu (4), Cross et al. (5), Teplick and Ruben (6) and Abraham (7), have recently assessed the state of the art in sepsis research prevention and treatment, the reasons why the trials of sepsis have invariably failed to prolong the lives of septic patients, the hazards involved in the future use of multidrug strategies in sepsis, and the con- tributions of animal models to the development effec- tive therapeutic regimens in humans. Reading through the extensive literature on sepsis research and treatment, it was surprising to realize that no less than 35 different anti-inflammatory agents and strategies have been rec- ommended, usually singly, to cope with post-infectious sequelae (in 1–13). It is however important to stress that, at the bedside, anti-inflammatory agents are too often administered to patients when the deleterious pathophys- iological cascades leading to septic shock and organ fail- ure have already been irreversibly initiated. Therefore, one cannot avoid assuming that the recommendations to test only one antagonist, at time, to suppress the patho- physiological cascades in sepsis and septic shock, might have been unrealistic to begin with and also erroneous. Presumably, these have been based on the concept that there might exist a single “omnipotent” pro-inflamma- tory agonist generated following microbial invasions of the blood stream, which is efficiently neutralized, on time, might inhibit the multiple pathophysiological cas- cades responsible for the sepsis syndrome. Also, the use of multidrug strategies (4, 5, 8, 13) has been ham- pered by reports warning against the hazards of combi- nation therapies in sepsis (4, 5, 16). Is it possible that, today, sepsis research has reached a dead end because of “flawed concept or faulty implementation?” (5). Results from animal models have clearly indicated that the inhibition of septic shock induced either by endotoxin (LPS), lipoteichoic acid (LTA), peptidogly- can (PPG) or by viable microbial cells, has been mostly successful only if the anti-inflammatory agent has been administered prior to microbial challenge. This strongly suggests that the main obstacle facing clinicians at the bedside is that once sepsis symptoms have appeared, it might already be too late to effectively prevent the pathophysiological cascades leading to tissue damage and organ failure. Therefore, strategies to prevent sep- tic shock and of additional post-infectious sequelae in humans should inonvolve distinct preventive measures especially in defined groups of high-risk patients (3–13).
Cationic peptides from leukocytes might kill bacteria by activating their autolytic enzymes causing bacteriolysis: why are publications proposing this concept never acknowledged?
Ginsburg I. Cationic peptides from leukocytes might kill bacteria by activating their autolytic enzymes causing bacteriolysis: why are publications proposing this concept never acknowledged?. Blood. 2001;97 (8) :2530-2531.Abstract
A large series of publications1-9 has proposed that cationic peptides from leukocytes kill bacteria primarily by causing a depolarization of their membranes leading to enhanced permeability. One group of cationic peptides from human neutrophils was even coined bactericidal/permeability-increasing proteins.3Surprisingly, however, none of a large series of other publications that had proposed a concept that cationic agents from neutrophils might be bactericidal also by virtue of their capacity to activate the bacterial autolytic wall enzymes (muramidases), leading to bacteriolysis and cell death,10-22 has ever been cited in any of the publications by the leading authors in this field of research.1-9 For the information of your readers, there exist a series of 16 publications since 1974 entitled “Effect of leukocyte hydrolases on bacteria” and several additional publications on the same subject under different titles, many of them published in journals covered by Medline; the references contain a selected list of these.10-22 24 These had proposed that many of the highly cationic agents either present in plasma or generated by activated phagocytes (eg, lysozymes, PLA2, elastase, cathepsin G, myeloperoxidase, bactericidal/permeability-increasing proteins, defensins, etc) might kill bacteria not simply by acting on the membranes to cause depolarization and enhanced permeability1-7 but also by an indirect mechanism. This involves a deregulation, by the cationic agents, of the anionic and amphiphilic regulators of the autolytic wall enzymes(muramidases) (lipoteichoic acid in Gram-positives and Forssman antigens in Gram-negatives)16 17 23-25 resulting in hydrolysis of the peptidoglycan, in bacteriolysis, and in cell death. It is of great clinical importance that the bacteriolysis-inducing activity of cationic agents mimics that of beta-lactam antibiotics.26 Furthermore, the observations that a variety of highly negatively charged, sulfated anionic agents can act as potent inhibitors of the cationic agent– and beta-lactam–induced bacteriolysis11 12 14 16 17 27-30further stress the importance of the autolytic systems in bacterial killing. This phenomenon might also be of great clinical significance especially in selecting measures to control postinfectious sequelae that undoubtedly are triggered by the release of bacterial components, especially following bacteriolysis. Regrettably, attempts to bring these issues to the awareness of the leading investigators in the field of cationic proteins1-9and of clinicians involved is the clinical aspects of sepsis control have not been successful. If the concept that cationic agents might be bactericidal also because of their bacteriolysis-inducing properties is reasonable and scientifically sound, it is expected that publications describing this phenomenon should be cited by authors studying the bactericidal effects of cationic agents. If on the other hand one deems that this concept is for some reason erroneous, nonsensical, and scientifically unacceptable, such publications should definitely be cited but properly discussed, challenged, and even also ridiculed. But it is totally unacceptable and unreasonable that such publications be simply ignored! Unfortunately, the avoidance of relevant citations and the disregard for concepts that might perhaps not “fit” current dogma and beliefs have reached epidemic levels. This is how pioneering publications proposing “novel approaches and ideas”16 17 29 30 to explain additional mechanisms of microbial killing might be lost forever. More importantly, these concepts will probably never reach the attention of clinicians interested in the pathogenesis of inflammation, infection, postinfectious sequelae, and the mechanisms of host defense.29-31 But what is even more disturbing, concerning, and unacceptable is that the expert referees selected by the editorial boards of journals and who should have been knowledgeable of the relevant literature failed to alert the authors to the existence of key publications on bacteriolysis so relevant to the subject of the papers and of the reviews they had been assigned to judge. Am I wrong to assume that the task of a journal's editorial board is to ensure that all viewpoints and ideas, both “conventional” and nonconventional, be equally represented? Excuses either that limitations to the number of references permissible were the reason for not citing basic and pioneering publications or that the authors had been “instructed” to discuss only a narrow field of research and to disregard others fields with direct relevance are unacceptable. A failure to give credit to relevant papers is also unacademic, self-defeating, unethical, and therefore unacceptable by all standards. Furthermore, are papers older than 15 years, or so, already passéand, therefore, unworthy of being acknowledged?
2000
Perioperative alterations in plasma endothelin-1 and echocardiographic correlates of right heart function
Amar D, Fleisher M, Leung DHY, Zhang H, Ginsburg I, Roistacher N. Perioperative alterations in plasma endothelin-1 and echocardiographic correlates of right heart function. Journal of Cardiothoracic and Vascular Anesthesia. 2000;14 (2) :140-143.Abstract
OBJECTIVE: To determine whether greater changes in plasma endothelin-1 (ET-1) concentrations and right ventricular systolic pressure occur after major thoracic surgery than after major abdominal operations. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Patients undergoing elective thoracotomies (n = 12) or laparotomies (n = 10). INTERVENTIONS: ET-1 was measured from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). Transthoracic echocardiography was performed before surgery and on postoperative day 2 to evaluate right-sided heart function. MEASUREMENTS AND MAIN RESULTS: After abdominal and thoracic surgery, systemic and estimated pulmonary vascular pressures were normal in both groups and unaffected by surgery. Plasma ET-1 concentrations decreased from baseline values during the first postoperative week with no differences between the groups. CONCLUSIONS: In patients without organic heart disease, plasma ET-1 levels do not increase in response to major abdominal or thoracic surgery. Whether or not plasma ET-1 concentrations are elevated in patients developing clinically significant postoperative pulmonary hypertension requires further study.
 Effects of diltiazem prophylaxis on the incidence and clinical outcome of atrial arrhythmias after thoracic surgery
Amar D, Roistacher N, Rusch VW, Leung DHY, Ginsburg I, Zhang H, Bains MS, Downey RJ, Korst RJ, Ginsberg RJ.  Effects of diltiazem prophylaxis on the incidence and clinical outcome of atrial arrhythmias after thoracic surgery. Journal of Thoracic and Cardiovascular Surgery. 2000;120 (4) :790-798.Abstract
OBJECTIVES: We sought to determine whether early prophylaxis with an L -type calcium channel blocker reduces the incidence and morbidity associated with atrial fibrillation/flutter and supraventricular tachyarrhythmia after major thoracic operations. METHODS: In this randomized, double-blind, placebo-controlled study, 330 patients were given either intravenous diltiazem (n = 167) or placebo (n = 163) immediately after lobectomy (> or =60 years) or pneumonectomy (> or =18 years) and orally thereafter for 14 days. The primary end point with respect to efficacy was a sustained (> or =15 minutes) or clinically significant atrial arrhythmia during treatment. RESULTS: Postoperative atrial arrhythmias (atrial fibrillation/flutter = 60; supraventricular tachyarrhythmias = 5) occurred in 25 (15%) of the 167 patients in the diltiazem group and 40 (25%) of the 163 patients in the placebo group (P = .03). When compared with placebo, diltiazem nearly halved the incidence of clinically significant arrhythmias (17/167 [10%] vs. 31/163 [19%], P = .02). The 2 groups did not differ in the incidence of other major postoperative complications or overall duration or costs of hospitalization. No serious adverse effects caused by diltiazem were seen. CONCLUSIONS: After major thoracic operations, prophylactic diltiazem reduced the incidence of clinically significant atrial arrhythmias in patients considered at high risk for this complication.
 Is a synergistic 'cross-talk' among microbial and host-derived agonists the main cause of tissue and organ injury in post-infectious and inflammatory sequelae?: Facts, paradoxes, and myths (a view point)
Ginsburg I.  Is a synergistic 'cross-talk' among microbial and host-derived agonists the main cause of tissue and organ injury in post-infectious and inflammatory sequelae?: Facts, paradoxes, and myths (a view point). Pathogenesis: the journal of mechanisms in disease processes. 2000;1 (4) :277-286. _preview-is_a_synergistic_cross-talk_2000.pdf
Cheminform abstract: novel anthraquinone derivatives with redox-active functional groups capable of producing free radicals by metabolism: are free radicals essential for cytotoxicity?
Barasch D, Zipori O, Ringel I, Ginsburg I, Samuni A, Katzhendler J. Cheminform abstract: novel anthraquinone derivatives with redox-active functional groups capable of producing free radicals by metabolism: are free radicals essential for cytotoxicity?. ChemInform. 2000;31 (6).Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a Full Text option. The original article is trackable via the References option.
  Are “Old” Pioneering Papers Passé?
Ginsburg I.   Are “Old” Pioneering Papers Passé?. Clinical Infectious Diseases. 2000;31 (1) :205.Abstract
SIR—I have recently read with much interest a paper by Taylor et al. entitled “Staging the Baboon Response to Group A Streptococci Administrated Intramuscularly: Descriptive Study of the Clinical Symptoms and Clinical Chemical Response Patterns” in Clinical Infectious Diseases [1]. While reading through the paper, it became apparent to me that articles published since 1959, which had described in great detail the pathophysiology of group A streptococcal injury (animal models), had not been cited in this article [2–7]. One review had already covered, in detail, many of the aspects related to your article [2], and had described a steep rise in glutamic oxaloacetic transaminase levels, sorbitol dehydro-genase (SOD), and in total lipids in animals injected with extracellular products [6]. In addition, Taylor et al. cite a study (reference 48) on theta toxin. Why not cite studies that show the effects of streptolysins S and O? Furthermore, the possible effects of streptolysin O (reference 52) and cysteine proteinase (reference 53) are mentioned. I would also like to note, for the interest of the readers, a paper by Ginsburg [8] that had shown that tumor cells could be killed and disintegrated, in a synergistic manner, by combining streptolysins S with a proteinase. The cysteine proteinase employed was isolated from streptococci and kindly supplied by Dr. Elliot from the Rockefeller Institute (New York City). Moreover, I would like to draw the attention of the authors to a more recent publication that has discussed in great detail synergistic mechanisms of cell injury. I refer to a review by Ginsburg and Kohen [9]. It is of great concern that the avoidance of citations of “old” and pioneering publications has assumed epidemic dimensions, especially among younger investigators. Today, although without abstracts, MEDLINE already offers citations from 1960 and later; however, a search for “older and obsolete” literature necessitates a review of the Index Medicus. This apparently might be too cumbersome for those who tend to read only titles and abstracts and not the full texts of articles. This dangerous trend in science is self-defeating, unscholarly, unacceptable, and also unethical. Unfortunately, this is how basic observations and ideas are “lost and buried for good.” The phrase “sic transit gloria mundi” is very appropriate. It is even more disturbing that the learned referees of the paper by Taylor et al., who have been expected to be knowledgeable of the older literature on streptococci, have failed to draw their attention to the existence of such “obsolete” and apparently unimportant publications. Unfortunately this is how basic observations are “rediscovered,” leading to the suffocation of the literature with “novel,” but redundant information. I shall greatly appreciate receiving your comments regarding these issues and am also looking forward to learn what might be the future policies of the editorial board of the journal regarding strategies taken to better cope with lack of appropriate citations to support scientific publications.
1999
 The biology of leukocyte-mediated proteolysis
Ginsburg I.  The biology of leukocyte-mediated proteolysis. Journal of Leukocyte Biology. 1999;66 (6) :1057.Abstract
Comment on The cell biology of leukocyte-mediated proteolysis. [J Leukoc Biol. 1999]
Signal-averaged P-wave duration does not predict atrial fibrillation after thoracic surgery
Amar D, Roistacher N, Zhang H, Baum MS, Ginsburg I, Steinberg JS. Signal-averaged P-wave duration does not predict atrial fibrillation after thoracic surgery. Anesthesiology. 1999;91 (1) :16-23.Abstract
BACKGROUND: Atrial fibrillation (AF) is the most common dysrhythmia seen early after major thoracic surgery but occurs infrequently after minor thoracic or other operations. A prolonged signal-averaged P-wave duration (SAPWD) has been shown to be an independent predictor of AF after cardiac surgery. The authors sought to determine whether a prolonged SAPWD alone or in combination with clinical or echocardiographic correlates predicts AF after elective noncardiac thoracic surgery. METHODS: Of the 250 patients enrolled, 228 were included in the final analysis. Preoperative SAPWD was obtained in 155 patients who had major thoracic surgery and in 73 patients undergoing minor thoracic or other operations who served as comparison control subjects. The SAPWD was recorded from three orthogonal leads using a sinus P-wave template. The filtered vector composite was used to measure total P-wave duration. Clinical, surgical, and echocardiographic parameters were collected and patients followed for 30 days after surgery for the development of symptomatic AF. RESULTS: Symptomatic AF developed in 18 of 155 (12%) patients undergoing major thoracic surgery and in 1 of 73 (1%) patients having minor thoracic or abdominal surgery, most commonly 2 or 3 days after surgery. In comparison with similar patients undergoing major thoracic surgery without AF, those who developed AF were older (66+/-8 vs. 62+/-10 yr; P = 0.04) but did not differ in SAPWD (145+/-17 vs. 147+/-16, ms) in standard electrocardiographic P-wave duration (105+/-7 vs. 107+/-10 mns), incidence of left-ventricular hypertrophy on 12-lead electrocardiography, male sex, history of hypertension, diabetes, or coronary heart disease. Thoracic-surgery patients at risk for postoperative AF did not differ from all other patients at low risk for AF in clinical or SAPWD parameters. CONCLUSIONS: Under the conditions of this study, SAPWD did not differentiate patients who did or did not develop AF after noncardiac thoracic surgery, and therefore its measurement cannot be recommended for the routine evaluation of these patients. Older age continues to be a risk factor for AF after thoracic surgery.
Hemolysis of human red blood cells induced by the combination of diethyldithiocarbamate (DDC) and divalent metals: Modulation by anaerobiosis, certain antioxidants and oxidants
Ginsburg I, Sadovnic M, Varani J, Tirosh O, Kohen R. Hemolysis of human red blood cells induced by the combination of diethyldithiocarbamate (DDC) and divalent metals: Modulation by anaerobiosis, certain antioxidants and oxidants. Free Radical Research. 1999;31 (2) :79-91.Abstract
The objective of the present communication is to describe the role played by combinations between diethydithiocarbamate (DDC) and divalent metals in hemolysis of human RBC. RBC which had been treated with DDC (10-50 microM) were moderately hemolyzed (about 50%) upon the addition of subtoxic amounts of Cu2+ (50 microM). However, a much stronger and a faster hemolysis occurred either if mixtures of RBC-DDC were immediately treated either by Co2+ (50 microM) or by a premixture of Cu2+ and Co2+ (Cu:Co) (50 microM). While Fe2+ and Ni2+, at 50 microM, initiated 30-50% hemolysis when combined with DDC (50 microM), on a molar basis, Cd2+ was at least 50 fold more efficient than any of the other metals in the initiation of hemolysis by DDC. On the other hand, neither Mn2+ nor Zn2+, had any hemolysis-initiating effects. Co2+ was the only metal which totally blocked hemolysis if added to DDC prior to the addition of the other metals. Hemolysis by mixtures of DDC + (Cu:Co) was strongly inhibited by anaerobiosis (flushing with nitrogen gas), by the reducing agents glutathione, N-acetyl cysteine, mercaptosuccinate, ascorbate, TEMPO, and alpha-tocopherol, by the PLA2 inhibitorbromophenacylbromide (BrPACBr), by tetracycline as well as by phosphatidyl choline, cholesterol and by trypan blue. However, TEMPO, BrPACBr and PC were the only agents which inhibited hemolysis induced by DDC: Cd2+ complexes. On the other hand, none of the classical scavengers of reactive oxygen species (ROS) employed e.g dimethylthiourea, catalase, histidine, mannitol, sodium benzoate, nor the metal chelators desferal and phenanthroline, had any appreciable inhibitory effects on hemolysis induced by DDC + (Cu:Co). DDC oxidized by H2O2 lost its capacity to act in concert either with Cu2+ or with Cd2+ to hemolyze RBC. While either heating RBC to temperatures greater than 37 degrees C or exposure of the cells to glucose-oxidase-generated peroxide diminished their susceptibility to hemolysis, exposure to the peroxyl radical from AAPH, enhanced hemolysis by DDC + (Cu:Co). The cyclovoltammetry patterns of DDC were drastically changed either by Cu2+, Co2+ or by Cd2+ suggesting a strong interaction of the metals with DDC. Also, while the absorbance spectrum of DDC at 280 nm was decreased by 50% either by Co2+, Cd2+ or by H2O2, a 90% reduction in absorbance occurred if DDC + H2O2 mixtures were treated either by Cu2+ or by Co2+, but not by Cd2+. Taken together, it is suggested that DDC-metal chelates can induce hemolysis by affecting the stability and the integrity of the RBC membrane, and possibly also of the cytoskeleton and the role played by reducing agents as inhibitors might be related to their ability to deplete oxygen which is also supported by the inhibitory effects of anaeobiosis.
Novel anthraquinone derivatives with redox-active functional groups capable of producing free radicals by metabolism: are free radicals essential for cytotoxicity?
Barasch D, Zipori O, Ringel I, Ginsburg I, Samuni A, Katzhendler J. Novel anthraquinone derivatives with redox-active functional groups capable of producing free radicals by metabolism: are free radicals essential for cytotoxicity?. European Journal of Medicinal Chemistry. 1999;34 (7-8) :597-615.Abstract
The mode of action of antitumour anthraquinone derivatives (i.e. mitoxantrone) is not clearly established yet. It includes, among others, intercalation and binding to DNA, bioreduction and aerobic redox cycling. A series of anthraquinone derivatives, with potentially bioreducible groups sited in the side chain, have been synthesized and biologically evaluated. Their redox and cytotoxic activities were screened. Derivatives which bear a 2-(dimethylamino)ethylamino substituent, known to confer high DNA affinity, demonstrated cytotoxicity but not redox activity (beside the anthraquinone reduction). Conversely, derivatives which showed redox activity were not cytotoxic toward the P388 cell line. The results suggest that bioreduction is not the main mode of action in the cytotoxicity of anthraquinones.
Antibacterial synergistic effect of chlorhexidine and hydrogen peroxide against Streptococcus sobrinus, Streptococcus faecalis and Staphylococcus aureus
Steinberg D, Heling I, Daniel I, Ginsburg I. Antibacterial synergistic effect of chlorhexidine and hydrogen peroxide against Streptococcus sobrinus, Streptococcus faecalis and Staphylococcus aureus. Journal of Oral Rehabilitation. 1999;26 (2) :151-156.Abstract
Chlorhexidine (CHX) and Hydrogen peroxide (HP) are potent antibacterial agents that are used in controlling dental plaque. However, both agents bear undesired side-effects. We have tested the hypothesis that an antibacterial synergistic effect can occur between the two agents against Streptococcus sobrinus, Streptococcus faecalis and Staphylococcus aureus. We have found that at several combinations of HP and CHX an antibacterial synergistic effect does occur, while at other combinations a on-significant synergism was noticed. No antagonism between the two agents was found in our experimental system. It can be postulated that the mechanism of this synergistic effect is via alteration of the bacterial cell-surface by CHX thereby allowing for an increased amount of HP to penetrate and to react with the intercellular organelles of the bacteria. These results suggest that CHX and HP can be of use in controlling the dental plaque in the oral cavity.

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