Evaluation of the Impact of Exposure To Heat and to By-Products of Combustion on the Health of Firefighters.

Firefighters are often exposed to high temperatures and by-products of combustion, which can affect their health. In this study, we assessed the impact of acute exposure of firefighters in fire simulators. Twenty male firefighters were exposed to fire simulators, and observed in four phases: pre-exposure (group 0, control) and after the end of the first (group 1), second (group 2), and fourth (group 3) weeks of training. Blood samples were collected and dosed to evaluate the response of the immune, inflammatory (C-reactive protein, IL6, and IL10), and endocrine systems (cortisone, total testosterone, free testosterone, SHBG, bioavailable testosterone, TSH, and free T4). In groups 0, 1, and 3, a thermographic evaluation was also carried out to study the temperature and body heat flow of the participants. Regarding the inflammatory process, an increase in C-reactive protein and a reduction in IL-10 were observed. With respect to hormonal markers, an increase in cortisol and reduced levels of free T4 and bioavailable testosterone were found after exposure, with recovery of testosterone levels in the final week of training. Thermoregulatory adaptation of the organism has been associated with changes in heat flow in the organism in people subjected to extreme temperatures, with emphasis on the performance of the lower limbs. Our findings demonstrate an inflammatory response with hormonal changes after exposure to fire and an adaptive response of thermal balance, which could aid understanding of the physiology of the human body in extreme situations.

Les sapeurs-pompiers (SP) sont régulièrement exposés à la chaleur et aux produits de combustion, qui peuvent avoir un retentissement sur leur santé. Nous avons évalué l'effet d'une exposition aiguë de 22 SP (tous des hommes) à incendie simulé grâce à la répétition à 4 reprises d'une même batterie d'examens (avant- T0, et à la fin des 1ère -T1 2ème - T2 et 3ème - T3 semaines d'entraînement). Des paramètres sanguins relatifs à l'inflammation et l'immunité (CRP, IL6, IL10) ainsi qu'au système endocrinien (cortisol, testostérones totale, libre et biodisponible, SHBG, TSH et T4 libre) étaient prélevés à chaque évaluation. Une étude thermographique, évaluant la température corporelle et le flux thermique corporel était réalisée à T0, T1 et T3. On constatait une augmentation de la CRP et une baisse de IL10. On observait une augmentation de la cortisolémie ainsi qu'une baisse de thyroxine libre et testostérone biodisponible, cette dernière se normalisant à T3. L'adaptation corporelle à la chaleur se traduit par une augmentation du flux thermique, en particulier aux membres inférieurs. Nous observons donc des réponses inflammatoire comme endocrinienne et une adaptation de la thermorégulation en cas d'exposition à un incendie, constatations pouvant contribuer à la compréhension de la physiologie humaine en situations extrêmes.

Fatigue Properties of Weakened and Non-weakened Roots Restored with CAD-CAM Milled Fiber Post, Prefabricated Fiber Post, or Cast Metal Post.

STATEMENT OF PROBLEM: Customized glass fiber posts using CAD-CAM technology have been suggested for restoring endodontically treated teeth. However, how weakened or non-weakened roots restored with anatomical CAD-CAM posts behave under cyclic fatigue is not clear. OBJECTIVE: To evaluate the load-bearing capacity under fatigue (fatigue failure load [FFL], the number of cycles for failure [CFF], and survival probabilities) and fracture pattern of weakened and non-weakened roots restored with CAD-CAM fiber post and cores, metal cast-post-core, and prefabricated fiber post and resin core. METHODS AND MATERIALS: A total of 60 crack-free bovine incisor roots (13 mm in length) with standard geometry were obtained and randomly allocated considering the factor "root condition" in two levels (weakened and non-weakened). Thus, half of the roots were weakened to obtain a wall thickness of 0.5 mm. After that, the endodontic treatment was executed, all roots embedded with acrylic resin and the specimens randomly allocated (n=10) considering the factor "post system" in three levels (CAD-CAM: CAD-CAM milled glass-fiber post and core; MBC: metallic-based post and core; and FRC: prefabricated glass-fiber post and composite resin core). The posts were luted with a dual-cure self-adhesive luting agent. Then, all teeth received a metallic crown. An initial load of 100 N at 20 Hz for 5000 cycles was applied for the step-stress fatigue test, followed by incremental steps of 50 N for 20,000 cycles each step, up to failure. A fracture pattern analysis was performed. RESULTS: CAD-CAM fiber post (FFL: 865 N; CFF: 311,000 cycles) presented similar fatigue performance (p>0.05) to FRC (FFL: 925 N; CFF: 335,000 cycles), with 100% of repairable fractures for non-weakened roots; however, both groups presented worse performance than MBC (p<0.05; FFL: 1265 N; CFF: 471,000 cycles) which led to 100% of catastrophic failures. No statistical difference was found in fatigue performance among the three systems for weakened roots (p>0.05; FFL: 1035-1170 N; CFF: 379,000-433,000 cycles), with a high rate of catastrophic failures. CONCLUSIONS: CAD-CAM fiber post presented similar fatigue performance to MBC and FRC approaches when restoring weakened roots. CADCAM was similar to FRC when restoring non-weakened roots, while MBC enhanced fatigue properties in this scenario.

Does the instrument used for the implant site preparation influence the bone-implant interface? A systematic review of clinical and animal studies.

This systematic review evaluates the influence of the instrument used for the implant site preparation on the bone-implant interface. Any type of clinical or animal study were searched for in MEDLINE/PubMed, ISI Web of Science, and SciVerse Scopus. Two independent reviewers screened titles/abstracts of articles and the full-text of potentially eligible studies. Comparisons of bone to implant contact and crestal bone loss were estimated using pairwise meta-analysis. Twenty-nine studies met the inclusion criteria. The instruments identified in the articles were conventional drills (CDs), osteotome (OT), piezoelectric device (PD), Er:YAG LASER (LS) and osseodensification drills (ODs). The meta-analysis on bone to implant contact suggested no difference between CDs and other techniques and the meta-analysis on crestal bone loss suggested no difference between CDs and PD. The survival of implants in sites prepared with CDs vs. OT or PD presented no significant differences. The use of PD provided lower inflammatory response and earlier bone formation when compared to CDs. ODs provided significant biomechanical improvement in comparison to CDs. LS did not provide any relevant improvement in comparison to CDs or PD. The influence of the instrument used for implant site preparation depended on the property evaluated.

Organometallic chemistry meets crystal engineering to give responsive crystalline materials.

Dynamically porous crystalline materials have been obtained by engineering organometallic molecules. This feature article deals with organometallic wheel-and-axle compounds, molecules with two relatively bulky groups (wheels) connected by a linear spacer. The wheels are represented by half-sandwich Ru(ii) moieties, while the spacer can be covalent or supramolecular in character. Covalent spacers are obtained using divergent bidentate ligands connecting two [(arene)RuX2] groups. Supramolecular spacers are instead obtained by exploiting the dimerization of COOH or C(O)NH2 groups appended to N-based ligands. A careful choice of ligand functional groups and X ligands leads to the isolation of crystalline materials with remarkable host-guest properties, evidenced by the possibility of reversibly capturing/releasing volatile guests through heterogenous solid-gas reactions. Structural correlations between the crystalline arrangement of the apohost and the host-guest compounds allow us to envisage the structural path followed by the system during the exchange processes.

A versatile salicyl hydrazonic ligand and its metal complexes as antiviral agents.

Acylhydrazones are very versatile ligands and their coordination properties can be easily tuned, giving rise to metal complexes with different nuclearities. In the last few years, we have been looking for new pharmacophores able to coordinate simultaneously two metal ions, because many enzymes have two metal ions in the active site and their coordination can be a successful strategy to inhibit the activity of the metalloenzyme. As a part of this ongoing research, we synthesized the acylhydrazone H2L and its complexes with Mg(II), Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). Their characterization, both in solution--also by means of potentiometric studies--and in the solid state, evidenced the ability of the o-vanillin hydrazone scaffold to give rise to different types of metal complexes, depending on the metal and the reaction conditions. Furthermore, we evaluated both the free ligand and its metal complexes in in vitro studies against a panel of diverse DNA- and RNA-viruses. In particular, the Mg(II), Mn(II), Ni(II) and Zn(II) complexes had EC50 values in the low micromolar range, with a pronounced activity against vaccinia virus.

Thio-urethanes improve properties of dual-cured composite cements.

This study aims at modifying dual-cure composite cements by adding thio-urethane oligomers to improve mechanical properties, especially fracture toughness, and reduce polymerization stress. Thiol-functionalized oligomers were synthesized by combining 1,3-bis(1-isocyanato-1-methylethyl)benzene with trimethylol-tris-3-mercaptopropionate, at 1:2 isocyanate:thiol. Oligomer was added at 0, 10 or 20 wt% to BisGMA-UDMA-TEGDMA (5:3:2, with 25 wt% silanated inorganic fillers) or to one commercial composite cement (Relyx Ultimate, 3M Espe). Near-IR was used to measure methacrylate conversion after photoactivation (700 mW/cm(2) × 60s) and after 72 h. Flexural strength and modulus, toughness, and fracture toughness were evaluated in three-point bending. Polymerization stress was measured with the Bioman. The microtensile bond strength of an indirect composite and a glass ceramic to dentin was also evaluated. Results were analyzed with analysis of variance and Tukey's test (α = 0.05). For BisGMA-UDMA-TEGDMA cements, conversion values were not affected by the addition of thio-urethanes. Flexural strength/modulus increased significantly for both oligomer concentrations, with a 3-fold increase in toughness at 20 wt%. Fracture toughness increased over 2-fold for the thio-urethane modified groups. Contraction stress was reduced by 40% to 50% with the addition of thio-urethanes. The addition of thio-urethane to the commercial cement led to similar flexural strength, toughness, and conversion at 72h compared to the control. Flexural modulus decreased for the 20 wt% group, due to the dilution of the overall filler volume, which also led to decreased stress. However, fracture toughness increased by up to 50%. The microtensile bond strength increased for the experimental composite cement with 20 wt% thio-urethane bonding for both an indirect composite and a glass ceramic. Novel dual-cured composite cements containing thio-urethanes showed increased toughness, fracture toughness and bond strength to dentin while demonstrating reduced contraction stress. All of these benefits are derived without compromising the methacrylate conversion of the resin component. The modification does not require changing the operatory technique.

Prolonged curing time reduces the effects of simulated pulpal pressure on the bond strength of one-step self-etch adhesives.

The aim of this study was to evaluate the effects of extended light-curing procedures on the microtensile bond strength (µTBS) of one-step self-etch adhesives (1-SEAs) submitted to simulated pulpal pressure. Coronal deep-dentin specimens were bonded using Clearfil S3 Bond (S3), Adper Easy Bond (EB), or G-Bond Plus (GB) following the manufacturers' recommendations and light-cured for 10 seconds or 40 seconds. The dentin-bonded specimens were stored in distilled water for 24 hours without pulpal pressure (control) or submitted to 20 cm H2O simulated pulpal pressure for 24 hours. The specimens were cut into matchsticks and subjected to µTBS testing. The data were statistically analyzed using the three-way analysis of variance and Tukey's tests (p<0.05). Debonded sticks were investigated through scanning electron microscopy. EB obtained higher bond strengths than GB and S3. However, prolonged light activation (40 seconds) provided higher µTBS for all adhesives when submitted to pulpal pressure. Conversely, pulpal pressure caused a drop in µTBS in EB and S3 when light-cured for 10 seconds. A mixed failure mode was mainly attained for the control groups, whereas the specimens submitted to pulpal pressure failed in the adhesive mode. The µTBS of GB was not affected by pulpal pressure when light-cured for 10 seconds. Adhesive was the most prevalent failure mode, except when light-cured for 40 seconds, which showed predominantly cohesive failure. Extended curing times improved the resistance of 1-SEAs to simulated pulpal pressure.

Analysis of federal process of care data reported from hospitals in rural westernmost North Carolina.

OBJECTIVE: To evaluate standardized process of care data collected on selected hospitals serving a remote, rural section of westernmost North Carolina. MATERIALS & METHODS: Centers for Medicare & Medicaid Services (CMS) data were retrospectively analyzed for 21 clinical parameters at Fannin Regional Hospital (FRH), Murphy Medical Center (MMC), and Union General Hospital (UGH). A binomial test was used to compare each study site to state (NC) and national (U.S.A.) average. RESULTS: Summary data showed FRH to have higher scores on a significant number of standardized clinical process of care measures compared to state (p < 0.05) and national (p < 0.005) averages. Too few process of care measures at UGH were significantly higher than state and national averages to conclude that differences were not due to Type I error. Similarly, at MMC too few process of care measures were significantly higher than national averages to conclude that observed differences were not attributable to Type I error. MMC did not achieve a significantly higher score on any process of care measure when compared to state averages. CONCLUSION: Despite limitations associated with summary data analysis, the CMS "Hospitals Compare" information suggests that process of care scores at FRH are significantly higher than the state and national average. As these hospital quality data are freely available to patients, it remains to be determined what impact this may have on hospital volume and/or market share in this region. Additional research is planned to identify process of care trends in this geographical area.

Antimicrobial and mutagenic properties of organotin(IV) complexes with isatin and N-alkylisatin bisthiocarbonohydrazones.

A new series of ligands is synthesised starting from thiocarbonohydrazide and isatin (H(2)itc) or N-alkylisatin (methyl, H(2)mtc; butyl, H(2)btc; pentyl, H(2)ptc); the X-ray structure of H(2)mtc is discussed. The bis imine ligands are reacted with diorganotin(IV) compounds, obtaining monometallic complexes. In order to establish unequivocally their coordination geometry, the X-ray structures of (C(2)H(5))(2)Sn(Hmtc)Cl.THF (THF, tetrahydrofuran) and (C(6)H(5))Sn(Hptc)Cl(2) are determined. In (C(2)H(5))(2)Sn(Hmtc)Cl.THF, the ligand results monodeprotonated and, essentially, monodentate through the sulphur atom, while in (C(6)H(5))Sn(Hptc)Cl(2) the ligand is still monodeprotonated but SNO tridentate. The organotin(IV) complexes of isatin and N-methylisatin exhibit good antibacterial activity, better than that of the corresponding N-butyl and N-pentylisatin derivatives. Gram positive bacteria are the most sensitive microorganisms. No growth inhibition of fungi is detected up to the concentration of 100 microg/ml. H(2)mtc shows mutagenic activity with and without metabolic activation, whereas no mutagenicity is found for its organotin complexes and for the other compounds.

Morphine but not fentanyl and methadone affects mitochondrial membrane potential by inducing nitric oxide release in glioma cells.

We have observed that treatment of human glioma cells with morphine in the nanomolar range of concentration affects the mitochondrial membrane potential. The effect is specific to morphine and is mediated by naloxone-sensitive receptors, and is thus better observed on glioma cells treated with desipramine; moreover, the mitochondrial impairment is not inducible by fentanyl or methadone treatment and is prevented by the nitric oxide (NO) synthase inhibitor L-NAME. We conclude that in cultured glioma cells, the morphine-induced NO release decreases the mitochondrial membrane potential, as one might expect based on the rapid inhibition of the respiratory chain by NO. The identification of new intra-cellular pathways involved in the mechanism of action of morphine opens additional hypotheses, providing a novel rationale relevant to the therapy and toxicology of opioids.

Synthesis and antimicrobial activity of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles.

A number of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles 6a-g (7b-f) were synthesized and tested for antibacterial and antifungal activity. Some of these compounds displayed antifungal activity at non-cytotoxic concentrations. Derivative 6c was 9 times more potent in vitro than miconazole and 20 times more selective against C. neoformans. 6c was also 8- and 125-fold more potent than amphotericin B and fluconazole, respectively. None of the compounds was active against bacteria. Preliminary structure-activity relationship (SAR) studies showed that the NO group at position 4 of the pyrazole ring is essential for the activity. Lipophilicity of the pyrazole moiety, N-alkyl chain length and planarity of the two heterocyclic rings appear to play a decisive role in modulating cytotoxicity and antifungal activity.

Preparations, structures, and electrochemical studies of aryldiazene complexes of rhenium: syntheses of the first heterobinuclear and heterotrinuclear derivatives with bis(diazene) or bis(diazenido) bridging ligands.

The mono- and binuclear aryldiazene complexes [Re(C6H5N=NH)(CO)5-nPn]BY4 (1-5) and [(Re(CO)5-nPn)2-(mu-HN=NAr-ArN=NH)](BY4)2 (6-12) [P = P(OEt)3, PPh(OEt)2, PPh2OEt; n = 1-4; Ar-Ar = 4,4'-C6H4-C6H4, 4,4'-(2-CH3)C6H3-C6H3(2-CH3), 4,4'-C6H4-CH2-C6H4; Y = F, Ph) were prepared by reacting the hydride species ReH(CO)5-nPn with the appropriate mono- and bis(aryldiazonium) cations. These compounds, as well as other prepared compounds, were characterized spectroscopically (IR; 1H, 31P, 13C, and 15N NMR data), and 1a was also characterized by an X-ray crystal structure determination. [Re(C6H5N=NH)(CO)(P(OEt)3)4]BPh4 (1a) crystallizes in space group P1 with a = 15.380(5) A, b = 13.037(5) A, c = 16.649(5) A, alpha = 90.33(5) degrees, beta = 91.2(1) degrees, gamma = 89.71(9) degrees, and Z = 2. The "diazene-diazonium" complexes [M(CO)3P2(HN=NAr-ArN identical to N)](BF4)2 (13-15, 17) [M = Re, Mn; P = PPh2OEt, PPh2OMe, PPh3; Ar-Ar = 4,4'-C6H4-C6H4, 4,4'-C6H4-CH2-C6H4] and [Re(CO)4(PPh2OEt)(4,4'-HN=NC6H4-C6H4N identical to N)](BF4)2 (16b) were synthesized by allowing the hydrides MH(CO)3P2 or ReH(CO)4P to react with equimolar amounts of bis(aryldiazonium) cations under appropriate conditions. Reactions of diazene-diazonium complexes 13-17 with the metal hydrides M2H2P'4 and M2'H(CO)5-nP"n afforded the heterobinuclear bis(aryldiazene) derivatives [M1(CO)3P2(mu-HN=NAr-ArN=NH)M2HP'4](BPh4)2 (ReFe, ReRu, ReOs, MnRu, MnOs) and [M1(CO)3P2(mu-HN=NAr-ArN=NH)M2'(CO)5-nP"n](BPh4)2 (ReMn, MnRe) [M1 = Re, Mn; M2 = Fe, Ru, Os; M2' = Mn, Re; P = PPh2OEt, PPh2OMe; P',P" = P(OEt)3, PPh(OEt)2; Ar-Ar = 4,4'-C6H4-C6H4, 4,4'-C6H4-CH2-C6H4; n = 1, 2]. The heterotrinuclear complexes [Re(CO)3(PPh2OEt)2(mu-4,4'-HN=NC6H4-C6H4N=NH)M(P(OEt)3)4(mu-4,4'-HN=NC6H4- C6H4N=NH)Mn(CO)3(PPh2OEt)2](BPh4)4 (M = Ru, Os) (ReRuMn, ReOsMn) were obtained by reacting the heterobinuclear complexes ReRu and ReOs with the appropriate diazene-diazonium cations. The heterobinuclear complex with a bis(aryldiazenido) bridging ligand [Mn(CO)2(PPh2OEt)2(mu-4,4'-N2C6H4-C6H4N2)Fe(P(OEt)3)4]BPh4 (MnFe) was prepared by deprotonating the bis(aryldiazene) compound [Mn(CO)3(PPh2OEt)2(mu-4,4'-HN=NC6H4-C6H4N=NH)Fe(4- CH3C6H4CN)(P(OEt)3)4](BPh4)3. Finally, the binuclear compound [Re(CO)3(PPh2OEt)2(mu-4,4'-HN=NC6H4-C6H4N2)Fe(CO)2(P(OPh)3)2](BPh4)2 (ReFe) containing a diazene-diazenido bridging ligand was prepared by reacting [Re(CO)3(PPh2OEt)2(4,4'-HN=NC6H4-C6H4N identical to N)]+ with the FeH2(CO)2(P(OPh)3)2 hydride derivative. The electrochemical reduction of mono- and binuclear aryldiazene complexes of both rhenium (1-12) and the manganese, as well as heterobinuclear ReRu and MnRu complexes, was studied by means of cyclic voltammetry and digital simulation techniques. The electrochemical oxidation of the mono- and binuclear aryldiazenido compounds Mn(C6H5N2)(CO)2P2 and (Mn(CO)2P2)2(mu-4,4'-N2C6H4-C6H4N2) (P = PPh2OEt) was also examined. Electrochemical data show that, for binuclear compounds, the diazene bridging unit allows delocalization of electrons between the two different redox centers of the same molecule, whereas the two metal centers behave independently in the presence of the diazenido bridging unit.

Diazo complexes of rhenium: preparations and crystal structures of the bis(dinitrogen), [Re(N2)2(PPh(OEt)2)4][BPh4] and methyldiazenido [ReCl(CH3N2)(CH3NHNH2)(PPh(OEt)2)3][BPh4] derivatives.

Depending on experimental conditions and the nature of the hydrazine, the reactions of ReCl3P3 [P = PPh(OEt)2] with RNHNH2 (R = H, CH3, tBu) afford the bis(dinitrogen) [Re(N2)2P4]+ (2+), dinitrogen ReClN2P4 (3), and methyldiazenido [ReCl(CH3N2)(CH3NHNH2)P3]+ (1+) derivatives. In contrast, reactions of ReCl3P3 [P = PPh(OEt)2, PPh2OEt] with arylhydrazines ArNHNH2 (Ar = Ph, p-tolyl) give the aryldiazenido cations [ReCl(ArN2)(ArNHNH2)P3]+ (4+) and [ReCl(ArN2)P4]+ (7+) and the bis(aryldiazenido) cations [Re(ArN2)2P3]+ (5+, 6+). These complexes were characterized spectroscopically (IR; 1H and 31P NMR), and the BPh4 complexes 1, 2, and 7 were characterized crystallographically. The methyldiazenido derivative [ReCl(CH3N2)(CH3NHNH2)(PPh(OEt)2)3][BPh4] (1) crystallizes in space group P1 with a = 15.396(5) A, b = 16.986(5) A, c = 11.560(5) A, alpha = 93.96(5) degrees, beta = 93.99(5) degrees, gamma = 93.09(5) degrees, and Z = 2 and contains a singly bent CH3N2, group bonded to an octahedral central metal. One methylhydrazine ligand, one Cl- trans to the CH3N2, and three PPh(OEt)2 ligands complete the coordination. The complex [Re(N2)2(PPh(OEt)2)4][BPh4] (2) crystallizes in space group Pbaa with a = 23.008(5) A, b = 23.367(5) A, c = 12.863(3) A, and Z = 4. The structure displays octahedral coordination with two end-on N2 ligands in mutually trans positions. [ReCl(PhN2)(PPh(OEt)2)4][BPh4] (7) crystallizes in space group P2(1)/n with a = 19.613(5) A, b = 20.101(5) A, c = 19.918(5) A, beta = 115.12(2) degrees, and Z = 4. The structure shows a singly bent phenyldiazenido group trans to the Cl- ligand in an octahedral environment. The dinitrogen complex ReClN2P4 (3) reacts with CF3SO3CH3 to give the unstable methyldiazenido derivative [ReCl(CH3N2)P4][BPh4]. Reaction of the methylhydrazine complex [ReCl(CH3N2)(CH3NHNH2)P3][BPh4] (1) with Pb(OAc)4 at -30 degrees C results in selective oxidation of the hydrazine, affording the corresponding methyldiazene derivative [ReCl(CH3N=NH)(CH3N2)P3][BPh4] (8). In contrast, treatment with Pb(OAc)4 of the related arylhydrazines [ReCl(ArN2)(ArNHNH2)P3][BPh4] (4) [P = PPh(OEt)2] gives the bis(aryldiazenido) complexes [Re(ArN2)2P3][BPh4] (5). Possible protonation reactions of Brønsted acids HX with all diazenides, 1, 4, 5, 6, and 8, were investigated and found to proceed only in the cases of the bis(aryldiazenido) complexes 5 and 6, affording, with HCl, the octahedral [ReCl(ArN=NH)(ArN2)P3][BPh4] or [ReCl(Ar(H)NN)(ArN2)P3][BPh4] (10) (Ar = Ph; P = PPh2OEt) derivative.

Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways.

The proinflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha are produced within the CNS, and, similar to the periphery, they have pleotrophic and overlapping functions. We have shown previously that TNF-alpha increases neuronal survival to a toxic influx of calcium mediated through neuronal N-methyl-d -aspartic acid (NMDA) glutamate-gated ion channels. This process, termed excitotoxicity, is a major contributor to neuronal death following ischemia or stroke. Neuroprotection by this cytokine requires both activation of the p55/TNF receptor type I and the release of TNF-alpha from neurons, and it is inhibited by the plant alkaloid nicotine. Here, we report that other inflammatory cytokines (IL-1 alpha, IL-1 beta, and IL-6) are also neuroprotective to excessive NMDA challenge in our system. Neuroprotection provided by IL-1 is distinct from TNF-alpha because it is inhibited by IL-1 receptor antagonist; it is not antagonized by nicotine, but it is inhibited by a neutralizing Ab to nerve growth factor (NGF). Similar to IL-1, IL-6-mediated neuroprotection is also antagonized by pretreatment with IL-1 receptor antagonist and it is not affected by nicotine. However, neutralizing anti-NGF only partially blocks IL-6-mediated protection. These studies support an important role for distinct but overlapping neuroprotective cytokine effects in the CNS.

Antimicrobial and mutagenic activity of some carbono- and thiocarbonohydrazone ligands and their copper(II), iron(II) and zinc(II) complexes.

Several mono- and bis- carbono- and thiocarbonohydrazone ligands have been synthesised and characterised; the X-ray diffraction analysis of bis(phenyl 2-pyridyl ketone) thiocarbonohydrazone is reported. The coordinating properties of the ligands have been studied towards Cu(II), Fe(II), and Zn(II) salts. The ligands and the metal complexes were tested in vitro against Gram positive and Gram negative bacteria, yeasts and moulds. In general, the bisthiocarbonohydrazones possess the best antimicrobial properties and Gram positive bacteria are the most sensitive microorganisms. Bis(ethyl 2-pyridyl ketone) thiocarbonohydrazone, bis(butyl 2-pyridyl ketone)thiocarbonohydrazone and Cu(H2nft)Cl2 (H2nft, bis(5-nitrofuraldehyde)thiocarbonohydrazone) reveal a strong activity with minimum inhibitory concentrations of 0.7 microgram ml-1 against Bacillus subtilis and of 3 micrograms ml-1 against Staphylococcus aureus. Cu(II) complexes are more effective than Fe(II) and Zn(II) ones. All bisthiocarbono- and carbonohydrazones are devoid of mutagenic properties, with the exception of the compounds derived from 5-nitrofuraldehyde. On the contrary a weak mutagenicity, that disappears in the copper complexes, is exhibited by monosubstituted thiocarbonohydrazones.

Conformational variety for the ansa chain of rifamycins: comparison of observed crystal structures and molecular dynamics simulations.

The antibiotic activity (via inhibition of DNA-dependent RNA polymerase, DDRP) of rifamycins has been correlated to the conformation of the ansa chain, which can be described by means of 17 torsion angles defined along the ansa backbone. It has been shown that favourable or unfavourable conformations of the ansa chain in rifamycin crystals are generally diagnostic of activity or inactivity against isolated DDRP. The principles of structure correlation suggest that the torsional variety observed in rifamycin crystals should mimic the dynamic flexibility of the ansa chain in solution. Twenty-six crystal structures of rifamycins are grouped into two classes (active and non-active). For each class the variance of the 17 ansa backbone torsion angles is analysed. Active compounds show a well-defined common pattern, while non-active molecules are more scattered, mainly due to steric constraints forcing the molecules into unfavourable conformations. The experimental distributions of torsion angles are compared to the torsional freedom of the ansa chain simulated by molecular dynamics calculations performed at different temperatures and conditions on rifamycin S and rifamycin O, which represent a typical active and a typical sterically constrained molecule, respectively. It is shown that the torsional variety found in the crystalline state samples the dynamic behaviour of the ansa chain for active compounds. The methods of circular statistics are illustrated to describe torsion angle distributions.

Comprehensive study on structure-activity relationships of rifamycins: discussion of molecular and crystal structure and spectroscopic and thermochemical properties of rifamycin O.

The mechanism of action of rifamycins against bacterial DNA-dependent RNA polymerase has been explained on the basis of the spatial arrangement of four oxygens which can form hydrogen bonds with the enzyme. Structural descriptors are derived from X-ray diffraction crystal structures of 25 active and nonactive rifamycins. Principal component analysis is used to find the combination of structural parameters which better discriminate between active and nonactive rifamycins. Two possible mechanisms of molecular rearrangement are described which can convert nonactive into active conformations. The energy involved for conformational rearrangements is studied by molecular modeling techniques. Methyl C34 is found to play a key role for determining the geometry of the pharmacophore. Rifamycin O, reported to be active, is obtained by oxidation of rifamycin B and is studied by X-ray single-crystal diffractometry, by solution IR and NMR spectroscopy, and by thermal analysis. Surprisingly the oxidation process is totally stereospecific, and an explanation is given based on solution spectroscopic evidence. The conformation found in the solid state is typical of nonactive compounds, and molecular mechanics calculations show that a molecular rearrangement to the active conformation would require about 15 kcal/mol. Thermal analysis confirms that rifamycin O has a sterically constrained conformation. Therefore, it is likely that the antibiotic activity of rifamycin O is due either to chemical modification prior to reaching the enzyme or to conformational activation.

Organotin complexes with pyrrole-2,5-dicarboxaldehyde bis(acylhydrazones). Synthesis, structure, antimicrobial activity and genotoxicity.

Mono- and bimetallic organotin complexes with pyrrole-2,5-dicarboxaldehyde bis(2-hydroxybenzoylhydrazone) (H5dfps) and pyrrole-2,5-dicarboxaldehyde bis(2-picolinoylhydrazone) (H3dfpp) were synthesized and characterized by IR, 1H and 119Sn NMR spectroscopy. X-ray analysis of the complex [Sn(H3dfps)(C6H5)2].(CH3)2SO revealed a pentacoordination around tin through a N,N,O terdentate ligand behaviour of the hydrazone. This complex is the most active compound, exhibiting MIC values of 3 and 12 micrograms/ml against Gram positive and Gram negative bacteria, respectively. None of the ligands or complexes produced DNA-damage in the Bacillus subtilis rec-assay or showed mutagenic activity in the Salmonella-microsome test.

Nicotine blocks TNF-alpha-mediated neuroprotection to NMDA by an alpha-bungarotoxin-sensitive pathway.

Excitotoxic neuronal death mediated by N-methyl-D-aspartate (NMDA) glutamate receptors can contribute to the extended brain damage that often accompanies trauma or disease. Both the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and nicotine have been identified as possible neuroprotective agents to NMDA assault. We find that TNF-alpha protection of a subpopulation of cultured cortical neurons to chronic NMDA-mediated excitotoxic death requires both the activation of the p55/TNFRI, but not p75/TNFRII, and the release of endogenous TNF-alpha. Nicotine protection to NMDA was mediated through an alpha-bungarotoxin-sensitive receptor. When coapplied, neuroprotection to NMDA by either TNF-alpha or nicotine was abolished but could be recovered with alpha-bungarotoxin. These results suggest that the cytokine TNF-alpha and alpha-bungarotoxin-sensitive nicotinic neurotransmitter receptors confer neuroprotection through potentially antagonistic pathways.

Modulation of the stimulus effects of morphine by d-amphetamine.

The stimulus effects of morphine and d-amphetamine coadministration were studied in rats. Place conditioning, drug discrimination, and taste conditioning were employed to assess the rewarding, discriminative, and aversive stimulus properties of both drugs. d-Amphetamine increased the rewarding and morphine-like discriminative stimulus effects of 1.25 mg/kg morphine. d-Amphetamine did not, however, change the aversive effects of 1.25 mg/kg morphine, or any effect of higher (5-20 mg/kg) morphine doses. Because the rewarding/discriminative properties and the aversive properties of a drug are considered the main attributes that regulate (facilitate and weaken, respectively) drug-seeking behavior, the present data are in keeping with clinical reports indicating that amphetamines are sometimes used by opiate abusers in an attempt to increase the effect obtained from poor-quality heroin.