Publications

Two sets of comb-grafted polymeric surfactants based on poly(methylhydrogen siloxane) (PHMS) and/or poly(dimethylsiloxane) (PHMS-PDMS) were prepd. by silylation of the active Si-H group with an active ω-vinyl group of specially designed undecenoic-polyethylene glycol esters (UPEG) to formation "newly-designed" polysiloxane-grafted-polyethylene glycol comb-copolymeric surfactants. The hydrophilic moieties are hooked to the hydrophobic backbone through a "spacer" (undecenoic acid). The variation in the surfactants' structures were in the length and d. of the grafted hydrophilic moieties, the chain length (DP) and nature of the hydrophobic backbone. The first 12 different polymeric surfactants (set 1), termed PHMS-UPEG, were ineffective emulsifiers with limited ability to stabilize oil-in-water emulsions. The second set of surfactants, named PHMS-PDMS-UPEG comb-grafted copolymers, significantly reduced the oil-water interfacial tension and efficiently stabilized several types of oil-in-water emulsions. The best emulsifier of this set (PHMS-PDMS-52-UPEG-45), seems to be one whose anchor backbone (PHMS-PDMS) dissolves (rather than spreads) in the oil phase, and whose stabilizing moieties are sufficiently long (45 EO units) and "hooked" to the silicone backbone at high d. (52% substitution). [on SciFinder(R)]

Immunohistochemistry and melanin bleaching were used to assess the expression of antigens identified by anti-S-100 and anti-HMB-45 antibodies on melanomas and intramucosal and blue nevi from the oral mucosa of 18 patients. Both antibodies reacted with cells in all three types of lesions, but there were differences in the expression of these antigens between the round and spindle cells within the lesions. In melanomas composed of round cells, the intensity and distribution of staining with HMB-45 was greater than with S-100. The opposite was true in melanomas composed of spindle-shaped cells, and one spindle-cell melanoma was HMB-45-negative. The round cells of intramucosal nevi expressed S-100 more intensely and more frequently than HMB-45. The spindle-shaped cells of blue nevi strongly expressed both S-100 and HMB-45. Whereas intradermal nevi from the skin do not express HMB-45, intramucosal nevi consistently express this antigen in the lesion and overlying mucosa. Oral melanomas composed of round and spindle-shaped cells show differences in their expression of S-100 and HMB-45 antigens, making the use of both antibodies complementary in the diagnosis of undifferentiated tumors.

The biochemical and biological properties of many of the pro-inflammatory agonists generated by catalase-negative hemolytic streptococci and by activated human phagocytes, and the mechanisms by which both cell types destroy tissues in infections and in inflammatory sites, are astonishingly similar. In the pre-antibiotic era, group A hemolytic streptococci, also known by the name Streptococcus pyogenes, were responsible for causing serious and life-threatening diseases, mainly in young individuals. These highly virulent agents cause suppurative lesions in virtually any part of the body, due perhaps to their ability to disseminate freely in tissues. They do this by virtue of their ability to elaborate numerous “spreading factors” and tissuedamaging agents. However, the hallmark of the streptococcus injuries is their ability to initiate non-suppurative sequelae (rheumatic fever, arthritis, chorea and glomerulonephritis). Activated phagocytes (neutrophils, eosinophils, macrophages) might also be involved in the pathogenesis of many inflammatory diseases because of their ability to generate and secrete numerous tissue-damaging agonists. It is perhaps paradoxical that both phagocytes and hemolytic streptococci possess adhesion molecules (Patarroyo, 199 1; Ofek et al., 1975; Hasty et al., 1992; Sela et al., 1993; Albelda et al., 1994), receptors for IgG and for IgA (Christensen et al., 1976; Ginsburg et al., 1982; Burova and Schalen, 1993), receptors for complement (Petty and Todd, 1993), receptors for a variety of serum proteins, and for fibronectin (Littenberg et al., 1987; Simpson et al., 1987; Sela et al., 1993). Both phagocytes (Greenwald and Jamison, 1977; Wright, 1982; Gallin et al., 1992) and streptococci (reviewed by Ginsburg, 1972, 1985, 1986), generate numerous spreading factors (hyaluronidase, DNAse, RNAse, proteinases, acid and neutral hydrolases and complement-destroying enzymes (Wexler et al.. 1985). All these agents might facilitate the movement of the cells through the endothelial and epithelial barriers and into the intercellular spaces, and to depolymerize extracellular matrix proteins and inflammatory exudates which, otherwise, might limit cell movement and their spread in the tissues of the host. The non-immunogenic hyaluronic acid capsule, present on the surface of virulent streptococci, mimics similar components also present on mammalian cells. This mimicry allows the streptococci to survive, unrecognized, by the phagocytic cells. Both streptococci (Ginsburg, 1972; Ginsburg, 1979b; Alouf, 1990; Bernheimer and Rudy, 1986) and phagocytes (Victor et al., 198 1; Kennedy and Becker, 1987; Gallin et al., 1992) generate potent membraneperforating agents (hemolysins, phospholipases) which are capable of killing host cells by boring “holes” in their plasma membranes. Both streptococci (Suzuki and Vogt, 1966; Vogt et al., 1983) and phagocytes (Elsbach and Weiss, 1992; Spitznagel, 1990; Lehrer, 1993) also generate a large variety of highly cationic arginine- and cysteine-rich bactericidal and cytocidal proteins. These agents are also capable of activating the respiratory burst in neutrophils (Ginsburg, 1987, 1989) and also of functioning as opsonins (Ginsburg, 1987, 1989). Polycations might also enhance the adherence of neutrophils to targets (Oseas et al., 1981) and thus facilitate delivery of the toxic agonist directly upon the targets. This property is also shared by streptococci possessing cell-bound streptolysin S (Ginsburg and Harris, 1965; Ginsburg and Varani, 1993). Phagocytes and hemolytic streptococci produce either cytokines (West, 1990; Badwey et al., 1991) or a pyrogenic super-antigen (erythrogenic toxin; see Hensler et al., 1993), respectively, which prime phagocytes to generate excessive amounts of reactive oxygen species (ROS) and of lipid mediators of inflammation. Streptococci also generate a surface amphiphile (lipoteichoic acid-LTA) (Ginsburg et al., 1988) which, like lipopolysaccharides (LPS) of Gramnegative rods (Forehand et al., 1989, 1991) also primes neutrophils to generate excessive amounts of ROS. A possible “genetical” linkage between the highly anti-phagocytic surface component, the M-protein of streptococci and human proteins, has been found (Fischetti et al., 1988). Seventy percent of the Mprotein molecule has a tertiary structure of coiled-coil, which is also a characteristic either of tropomyosin, myosin or fibrinogen. Group A hemolytic streptococci also possess two sets of antigens which crossreact with human heart, kidney, brain, skin, myosin and perhaps also with leukocytes (Ayoub and Kaplan, 1991: Stollerman, 1975, 1991; Trentin, 1967; Kaplan, 1967; Ginsburg, 1972; Krisher and Cunningham, 1985; Swerlick and Cunningham. 1986). This led to the hypothesis that the development of crossreactive immunity, in susceptible hosts (Stollerman, 1975, 1991) might be responsible for the pathogenesis of rheumatic fever. arthritis, chorea and nephritis, that are the hallmarks of the post-streptococcal sequelae. Since the crossreactive antibodies isolated from rheumatic fever patients were not cytotoxic to cardiac tissue, their role, if any, in the pathogenesis of tissue damage remains to be established. Most importantly, however, both activated phagocytes and the catalase-negative hemolytic streptococci generate large amounts of H2 O2 (Avery and Morgan, 1924; Ginsburg, 1972; Halliwell and Gutteridge, 1989; Klebanoff and Clark, 1978; Klebanoff, 1992). It therefore stands to reason that both phagocytes and streptococci might cause cellular damage by a tight and wellorchestrated and synergistic collaboration among their secreted agonists (see below). Furthermore, extracellular products elaborated by both phagocytes and streptococci during their encounter in infectious sites, might also interact to amplify cellular damage. Such interactions might take place when H20Z generated by streptococci might be effectively utilized by neutrophils of patients suffering of chronic granulomatous disease of childhood (CGD), which possess a defective NADPH oxidase (Smith and Curnutte, 1991). Such an interaction might not only restore the ability of the CGD phagocytes to kill bacteria, but might also, paradoxically, lead to enhanced cellular damage provided that additional agonists are also present (see below). It is thus tempting to speculate that, mainly from functional and perhaps also from evolutionary points of view, hemolytic streptococci and other toxigenic bacteria (Clostridiae) might perhaps be considered “forefathers of modern phagocytes”. However, it should also be emphasized that evolution displays many examples where basic and parallel biological phenomena might appear in phyla far removed from each other, with no apparent common genetical basis. This emphasizes the successfulness of the strategy, since two totally separate evolutionary pathways have led to it.

A method for calculating decay rates of vibrational modes in large polyatomic systems is proposed and tested. The high frequency excited vibration is treated quantum mechanically, and the soft modes are described classically. The initial state is described by the hybrid quantum/classical self-consistent-field (SCF) approximation. The formalism is based-on a golden-rule expression. The driving potential is the difference between the full Hamiltonian and the mean field Hamiltonian (SCF) causing the decay of the initial state to final mixed quantum/classical ;SCF states. These states are calculated using an extension of the usual static mean-field techniques to systems with mixed quantum and classical degrees of freedom. The formalism for obtaining the mean-field states and calculating the decay rates is presented, and the method is applied to a diatomic molecule treated quantum mechanically, embedded in a 1D model for a. rare gas cluster treated classically. The dependence of the eigenenergies of the quantum and the decay rates with temperature is studied. The influence on the system size is also presented and compared with the prediction of the isolated binary collision model. The effect of a change in the linear density of the cluster on the eigenenergies of the vibrational mode is presented.

Monkey kidney epithelial cells, labeled with chromium and grown in culture, were killed in a synergistic manner when subtoxic amounts of ethanol were combined either with subtoxic amounts of glucose oxidase-generated hydrogen peroxide, or with mixtures of peroxide and with 2,2'-Azo-bis (2-amidinopropane)HCl (AAPH)-generated peroxyl radical. A further enhancement of cytotoxicity occurred when subtoxic amounts of trypsin were added to mixtures of all three agents. While ethanol alone caused shrinkage of the monolayers and cell rounding, no visible cytotoxic changes were observed. Hydrogen peroxide at the concentrations used (about 1 mM), caused only some cell rounding. On the other hand, cells exposed simultaneously to ethanol and to H2O2 developed extensive membrane damage characterized by the formation of large polar blebs, which is compatible with altered membrane permeability. The presence of trypsin markedly enhanced cellular cytotoxicity induced by mixtures of peroxide, peroxyl radical, and ethanol. This could markedly be depressed by catalase and by dimethylthiourea. The tissue culture model described might serve to further investigate the role played by synergy among oxidants and a variety of membrane-damaging agents, and by xenobiotics in tissue damage induced by inflammatory processes.

Photodissociation of ICN by W excitation in solid and liquid Ar is studied by molecular dynamics simulations. The focus is on the differences between the cage effects on the CN photoproduct in the two phases, and on the excited state isomerization ICN* –> INC* dynamics in the solid matrix. Nonadiabatic transitions are neglected in this first study. The main results are: (1) No cage exit of the CN product is found in solid Ar, even in simulations at temperatures close to melting and for large excess energies. The result is in accord with recent experiments by Fraenkel and Haas. This should be contrasted with the large cage-exit probabilities found in many systems for atomic photofragments. The result is interpreted in terms of geometric and energy transfer considerations. It is predicted that complete caging of diatomic and larger photofragments will be typically the case for photodissociation in rare-gas matrices. (2) Almost 100% cage-exit probability for the CN product is found for ICN photolysis on the (II1)-I-1 potential surface in liquid Ar. On the other hand, photolysis on (II0+)-I-3 potential surface does not lead to cage exit on a time scale of 15 ps. The large differences between the reaction in the solid and in the liquid, and between the behavior of the process on the (II0+)-I-3 and the (II1)-I-1 potentials, respectively in the liquid, are interpreted. (3) CN rotational dynamics and subsequent relaxation leads to isomerization int he excited electronic states. On the (II0+)-I-3 potential surface one finds after t greater than or similar to 0.5 ps roughly equal amounts of the ICN and INC isomers. On the (II1)-I-1 surfaces only INC is found after t greater than or similar to 3.5 ps. This is explained in terms of the barriers for CN rotation in the two excited states, and in terms of time scales for rotational relaxation. The results throw light on the differences between cage effects for photochemical reactions in solid and in liquid solution, and on cage-induced isomerization dynamics in solid matrices.

The photodissociation dynamics of HCl in the clusters Ar2-HCl and Ar-HCl is studied in order to explore the cluster size effect. A quasi classical trajectory approach is employ to simulate the photofragmentation dynamics. interesting manifestations of the cage effect are found in the light and the heavy atom kinetic energy distributions, with important differences between the two clusters. The Ar and Cl distributions provide separate information on dynamical events which cannot be resolved in the hydrogen distribution. Only two different excitation wavelengths are used in the simulations. The cage effect is found to be strongly dependent on the wavelength employed to excite the HCl molecule. This is so to the extent that the trend of an increasing cage effect with the cluster size is reversed for the smaller wavelength. New types of resonance behavior are observed for the hydrogen motion in Ar2-HCl compared with the Ar-HCl cluster. An interesting difference between Ar-HCl and Ar2-HCl is that, in the latter case, Ar2 can form as product of the photodissociation, with a high yield for the two wavelengths. The dynamics of the process and the implications of the results are discussed.

Appeared also in his 'An Alternative Path to Modernity' (2000).

Comment on Effect of lysophosphatidic acid on motility, polarisation and metabolic burst of human neutrophils. [FEMS Immunol Med Microbiol. 1994]

Attempts have been made to produce and use new polymeric surfactants based on polysiloxane-graft-poly(oxyethylene) for stabilization of water-in-oil-in-water (W/O/W) multiple emulsions. Hydrophobic comb-grafted copolymers have been used at the inner interface to obtain stable small droplet size water-in-oil emulsions. Hydrophilic comb-grafted copolymers with similar structures but with high d. grafting and long poly(oxyethylene) chains have been used to stabilize the outer interface of the W/O/W emulsion. Stable multiple emulsion formulations with very slow release rates can be obtained when using the two types of silicone emulsifier. [on SciFinder(R)]