Nitrogen- and carbon-based isomerism in the copper(II) complexes of 6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine

A number of N- and C-based diastereomeric copper(II) complexes of the pendant-arm macrocyclic hexaamines trans- and cis-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine (L-1 and L-2) have been isolated and characterised. The crystal structures of the complexes RRSS-[CuL1(OH2)(2)][ClO4](2), SSRR-[Cu(H2L1)(OClO3)(2)]-[ClO4](2) . 2H(2)O RSRS-[CuL1(OClO3)]ClO4, RSRS-[CuL2(OClO3)]ClO4 and RRSS-[Cu(H2L2)(OClO3)(2)][ClO4](2) have been determined. Some unusual structural and spectroscopic variations are found across this series of diastereomers. The protonation constants of the pendant primary amines are dependent on the relative dispositions of the adjacent macrocyclic secondary amine H atoms, which is indicative of intramolecular hydrogen-bonding interactions.

Structural and electron self-exchange rate variations in isomeric (hexaamine)cobalt(III/II) complexes

The syntheses and characterisation of the new macrocyclic hexaamine trans-(5(S),7(S),12(R),14(R)-tetramethyl)-1,4,8,11-tetraazacyclotetradecane-6,13-diamine (L-6) and its Co-III complex are reported. The X-ray crystal structural analyses of [CoL6]Cl-2(ClO4) [monoclinic, space group C2/c, a = 16.468(3) Angstrom, b = 9.7156(7) Angstrom, c = 15.070(3) Angstrom, beta = 119.431(8)degrees, Z = 4] and the closely related cis-diamino-substituted macrocyclic complex [CoL2](ClO4)(3) . 2H(2)O (L-2 = cis-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine) [orthorhombic, space group Pna2(1), a = 16.8220(8) Angstrom, b = 10.416(2) Angstrom, c = 14.219(3) Angstrom, Z = 4] reveal significant variations in the observed Co-N bond lengths and coordination geometries, which may be attributed to the trans or cis disposition of the pendent primary amines. The Co-III/II self-exchange electron transfer rate constants for these and other closely related hexaamines have been determined, and variations of some 2 orders of magnitude are found between pairs of trans and cis isomeric Co-III complexes.

Extracellular calcium stimulates Na+-dependent putrescine uptake in B16 melanoma cells

The regulation of putrescine transport in difluoromethylornithine-treated B16 melanoma cells by extracellular Ca2+ has been investigated. It was found that physiological concentrations of Ca2+ were essential for optimum uptake of putrescine and spermidine. Mg2+, albeit at higher concentrations, also could potentiate polyamine transport. The maximum rate of putrescine uptake increased from 1698 +/-: 67 pmol/min/mg DNA in the absence of Ca2+ to 3100 +/- 98 pmol/min/mg DNA in the presence of 0.5 mM Ca2+. There was no change in K-m. While Ca2+ enhanced transport of both putrescine and spermidine it did not affect the uptake of deoxyglucose, thymidine or leucine. Putrescine did not alter Ca2+ fluxes suggesting that the two cations do not share a common transport system. The effects of Ca2+ on putrescine uptake appeared to be mediated extracellularly firstly because Ca2+ did not potentiate putrescine uptake in the presence of A23187 and secondly, because the effects of Ca2+ were completely inhibited by the lanthanide Tb3+, which binds to calcium-dependent proteins and does not readily cross biological membranes. Ca2+ did not affect putrescine transport in the absence of extracellular Na+. Moreover, the rate of putrescine uptake in the absence of Ca2+ was similar to that in the absence of extracellular Na+. The results from this study indicate that polyamine transport is stimulated by extracellular Ca2+ and suggest that Ca2+ is required for activity of the Na+-dependent transporter only. This transporter appears to possess a regulatory binding site for divalent cations. (C) 1997 Elsevier Science Ltd.

Cationic technetium and rhenium complexes with pendant carbohydrates

Three carbohydrate conjugated dipicolylamine chelators, 2-bis(2-pyridinylmethyl)amino)ethyl 1-deoxy-1-thio-beta-D-glucopyranoside (L(1)), 2-bis(2-pyridinylmethyl)amino)ethyl-beta-D-glucopyranoside (L(2)), and 2-bis(2-pyridinylmethyl)amino)carboxamide-N-(2-amino-2-deoxy-D-glucopyranose) (L(3)) were complexed to the [M(Co)(3)](+) core (M=Tc, Re) and the properties of the resulting complexes were investigated. Synthesis and characterization of the chelator 2-bis(2-pyridinylmethyl)amino)ethyl 1-deoxy-1-thio-beta-D-glucopyranoside (L(1)) and the corresponding Re complex are reported. All chelators were radiolabeled in high yield with [(99)mTc(CO)(3)(H(2)O)(3)](+) ( > 98%) and [(186)Re(CO)(3)(H(2)O)(3)](+) ( > 80%). The chelators and Re-complexes were determined to not be substrates for the glucose metabolism enzyme hexokinase. However, the biodistribution of each of the (99m)Tc complexes demonstrated fast clearance from most background tissue, including >75% clearance of the activity in the kidneys and the liver within 2 h post-injection. (C) 2010 Elsevier Ltd. All rights reserved.

Spin-orbit mixing and nephelauxetic effects in the electronic spectra of nickel(II)-encapsulating complexes involving nitrogen and sulfur donors

A study of spin-orbit mixing and nephelauxetic effects in the electronic spectra of nickel(II)-encapsulating complexes involving mixed nitrogen and sulfur donors is reported. As the number of sulfur donors is systematically varied through the series [Ni(N6-xSx)](2+) (x = 0-6), the spin-forbidden (3)A(2)g --> E-1(g) and (3)A(2g) --> (1)A(1g) transitions undergo a considerable reduction in energy whereas the spin-allowed transitions are relatively unchanged. The [Ni(diAMN(6)sar)](2+) and [Ni(AMN(5)Ssar)](2+) complexes exhibit an unusual band shape for the (3)A(2g) --> T-3(2g) transition which is shown to arise from spin-orbit mixing of the E spin-orbit levels associated with the E-1(g) and T-3(2g) states. A significant differential nephelauxetic effect also arises from the covalency differences between the t(2g) and e(g) orbitals with the result that no single set of Racah B and C interelectron repulsion parameters adequately fit the observed spectra. Using a differential covalency ligand-field model, the spectral transitions are successfully reproduced with three independent variables corresponding to 10Dq and the covalency parameters f(t) and f(e), associated with the t(2g) and e(g) orbitals, respectively. The small decrease in f(t) from unity is largely attributed to central-field covalency effects whereas the dramatic reduction in f(e) with increasing number of sulfur donors is a direct consequence of the increased metal-ligand covalency associated with the sulfur donors. Covalency differences between the t(2g) and e(g) orbitals also result in larger 10Dq values than those obtained simply from the energy of the (3)A(2g) --> T-3(2g) spin-allowed transition.

Proton transport model in the ionosphere .1. Multistream approach of the transport equations

The suprathermal particles, electrons and protons, coming from the magnetosphere and precipitating into the high-latitude atmosphere are an energy source of the Earth's ionosphere. They interact with ambient thermal gas through inelastic and elastic collisions. The physical quantities perturbed by these precipitations, such as the heating rate, the electron production rate, or the emission intensities, can be provided in solving the kinetic stationary Boltzmann equation. This equation yields particle fluxes as a function of altitude, energy, and pitch angle. While this equation has been solved through different ways for the electron transport and fully tested, the proton transport is more complicated. Because of charge-changing reactions, the latter is a set of two-coupled transport equations that must be solved: one for protons and the other for H atoms. We present here a new approach that solves the multistream proton/hydrogen transport equations encompassing the collision angular redistributions and the magnetic mirroring effect. In order to validate our model we discuss the energy conservation and we compare with another model under the same inputs and with rocket observations. The influence of the angular redistributions is discussed in a forthcoming paper.

Targeted drug delivery to the skin and deeper tissues: Role of physiology, solute structure and disease

1. Drug delivery through the skin has been used to target the epidermis, dermis and deeper tissues and for systemic delivery, The major barrier for the transport of drugs through the skin is the stratum corneum, with most transport occurring through the intercellular region, The polarity of the intercellular region appears to be similar to butanol, with the diffusion of solutes being hindered by saturable hydrogen bonding to the polar head groups of the ceramides, fatty acids and other intercellular lipids, Accordingly, the permeability of the more lipophilic solutes is greatest from aqueous solutions, whereas polar solute permeability is favoured by hydrocarbon-based vehicles. 2. The skin is capable of metabolizing many substances and, through its microvasculature, limits the transport of most substances into regions below the dermis. 3. Although the flux of solutes through the skin should be identical for different vehicles when the solute exists as a saturated solution, the fluxes vary in accordance with the skin penetration enhancement properties of the vehicle. It is therefore desirable that the regulatory standards required for the bioequivalence of topical products include skin studies. 4. Deep tissue penetration can be related to solute protein binding, solute molecular size and dermal blood flow. 5. Iontophoresis is a promising area of skin drug delivery, especially for ionized solutes and when a rapid effect is required. 6. In general, psoriasis and other skin diseases facilitate drug delivery through the skin. 7. It is concluded that the variability in skin permeability remains an obstacle in optimizing drug delivery by this route.

A semi-empirical approach to optimise the quantity of drying aids required to spray dry sugar-rich foods

A semi-empirical linear equation has been developed to optimise the amount of maltodextrin additive (DE 6) required to successfully spray dry a sugar-rich product on the basis of its composition. Based on spray drying experiments, drying index values for individual sugars (sucrose, glucose, frutose) and citric acid were determined, and us;ng these index values an equation for model mixtures of these components was established. This equation has been tested with two sugar-rich natural products, pineapple juice and honey. The relationship was found to be valid for these products.

Efficacy of the tubercidin antileishmania action associated with an inhibitor of the nucleoside transport

Tubercidin (TUB) is an adenosine analog with potent antiparasite action, unfortunately associated with severe host toxicity. Prevention of TUB toxicity can be reached associating nitrobenzylthioinosine (NBMPR), an inhibitor of the purine nucleoside transport, specifically target to the mammal cells. It was demonstrated that this nucleoside transport inhibitor has no significant effect in the in vitro uptake of TUB by Schistosoma mansoni and Trypanosoma gambiense. Seeking to evaluate if the association of these compounds is also effective against leishmania, we analyzed the TUB-NBMPR combined treatment in in vitro cultures of promastigote forms of Leishmania (L.) amazonensis, Leishmania (L.) chagasi, Leishmania (L.) major, and Leishmania (V.) braziliensis as well as in cultures of amastigote forms of L. (L.) amazonensis, mice macrophages infected with L. (L.) amazonensis, and in vivo tests in BALB/c mice infected with L. (L.) amazonensis. We demonstrated that TUB-NBMPR combined treatment can be effective against leishmania cells protecting mammalian cells from TUB toxicity.

Molybdenum carbonyl complexes of pendant-arm polyazamacrocycles

Molybdenum hexacarbonyl reacted with the pendant-arm macrocycles 10-methyl-1,4,8, 12-tetraazacyclopentadecane-10-amine (L-1) and trans-6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6, 13-diamine (L-2) in the absence of air to form complexes fac-[MoL1(CO)(3)] and [Mo2L2(CO)(8)] respectively. The mononuclear complex has the macrocycle bound in a tridentate manner, including the pendant primary amine, whereas the dinuclear complex exhibits a bridging bis(didentate) co-ordination mode, again involving the pendant primary amines. Structures have been defined by crystal structure analyses. The preferential binding of the pendant primary amines rather than additional secondary amines parallels similar behaviour observed earlier with some mercury(II) and rhodium(III) complexes, and points to the important general role of this pendant, despite being fused directly to the macrocyclic ring, in metal-ion binding.

Protein disulfide isomerase (PDI) associates with NADPH oxidase and is required for phagocytosis of Leishmania chagasi promastigotes by macrophages

PDI, a redox chaperone, is involved in host cell uptake of bacteria/viruses, phagosome formation, and vascular NADPH oxidase regulation. PDI involvement in phagocyte infection by parasites has been poorly explored. Here, we investigated the role of PDI in in vitro infection of J774 macrophages by amastigote and promastigote forms of the protozoan Leishmania chagasi and assessed whether PDI associates with the macrophage NADPH oxidase complex. Promastigote but not amastigote phagocytosis was inhibited significantly by macrophage incubation with thiol/PDI inhibitors DTNB, bacitracin, phenylarsine oxide, and neutralizing PDI antibody in a parasite redox-dependent way. Binding assays indicate that PDI preferentially mediates parasite internalization. Bref-A, an ER-Golgi-disrupting agent, prevented PDI concentration in an enriched macrophage membrane fraction and promoted a significant decrease in infection. Promastigote phagocytosis was increased further by macrophage overexpression of wild-type PDI and decreased upon transfection with an antisense PDI plasmid or PDI siRNA. At later stages of infection, PDI physically interacted with L. chagasi, as revealed by immunoprecipitation data. Promastigote uptake was inhibited consistently by macrophage preincubation with catalase. Additionally, loss-or gain-of-function experiments indicated that PMA-driven NADPH oxidase activation correlated directly with PDI expression levels. Close association between PDI and the p22phox NADPH oxidase subunit was shown by confocal colocalization and coimmunoprecipitation. These results provide evidence that PDI not only associates with phagocyte NADPH oxidase but also that PDI is crucial for efficient macrophage infection by L. chagasi. J. Leukoc. Biol. 86: 989-998; 2009.

Association of the UGT1A1-53(TA)(n) polymorphism with L-thyroxine doses required for thyrotropin suppression in patients with differentiated thyroid cancer

There is a considerable interindividual variation in L-thyroxine [ 3,5,3`,5`-tetraiodo-l-thyronine (T(4))] dose required for thyrotropin (thyroid-stimulating hormone) suppression in patients with differentiated thyroid cancer. To investigate whether uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)-mediated T(4) glucuronidation in liver affects T(4) dose, we genotyped 101 patients for the common UGT1A1-53(TA)(n) polymorphism and compared T(4) doses among patients having zero (5/6 and 6/6 genotypes), one (6/7 genotype), or two (7/7 and 7/8 genotypes) copies of the low-expression (TA) 7 and (TA) 8 alleles. A significant trend for decreasing T(4) dose with increasing number of copies of (TA)(7) and (TA)(8) (P = 0.037) and significant difference in T(4) dose across the UGT1A1-53(TA)(n) genotypes (P = 0.048) were observed, despite considerable overlap of T(4) doses among different genotypes. These results are consistent with reduced T(4) glucuronidation in patients with low-expression (TA) 7 and (TA) 8 alleles and provide the first evidence for association between UGT1A1-53(TA)(n) and T(4)-dose requirement for thyroid-stimulating hormone suppression in a natural clinical setting. Pharmacogenetics and Genomics 21: 341-343 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Pharmacogenetics and Genomics 2011, 21: 341-343

Executive dysfunction in children and adolescents with temporal lobe epilepsy: Is the Wisconsin Card Sorting Test enough?

The Wisconsin Card Sorting Test (WCST) is the gold standard in the evaluation of executive dysfunction (ED) in patients with temporal lobe epilepsy (TLE). We evaluated 35 children with TLE and 25 healthy controls with the WCST and with a more comprehensive battery. Among the children with TLE, 77.14% showed impairment on the WCST. On other tests (Wechsler Intelligence Scale for Children-Digit Forward, Matching Familiar Figures Test, Trail Making Test, Word Fluency, Finger Windows, and Number-Letter Memory), impairment was demonstrated in 94.29%. The authors concluded that the WCST is a good paradigm to measure executive impairment in children with TLE: however, it may be not enough. Evaluation performed only with the WCST not only underestimated the number of patients with ED, but also missed relevant information regarding the type of ED. (C) 2009 Elsevier Inc. All rights reserved.