Factors Related to the Selection of Surgical Versus Percutaneous Revascularization in Diabetic Patients With Multivessel Coronary Artery Disease in the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) Trial

Objectives We evaluated demographic, clinical, and angiographic factors influencing the selection of coronary artery bypass graft (CABG) surgery versus percutaneous coronary intervention (PCI) in diabetic patients with multivessel coronary artery disease (CAD) in the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial. Background Factors guiding selection of mode of revascularization for patients with diabetes mellitus and multivessel CAD are not clearly defined. Methods In the BARI 2D trial, the selected revascularization strategy, CABG or PCI, was based on physician discretion, declared independent of randomization to either immediate or deferred revascularization if clinically warranted. We analyzed factors favoring selection of CABG versus PCI in 1,593 diabetic patients with multivessel CAD enrolled between 2001 and 2005. Results Selection of CABG over PCI was declared in 44% of patients and was driven by angiographic factors including triple vessel disease (odds ratio [OR]: 4.43), left anterior descending stenosis >= 70% (OR: 2.86), proximal left anterior descending stenosis >= 50% (OR: 1.78), total occlusion (OR: 2.35), and multiple class C lesions (OR: 2.06) (all p < 0.005). Nonangiographic predictors of CABG included age >= 65 years (OR: 1.43, p = 0.011) and non-U.S. region (OR: 2.89, p = 0.017). Absence of prior PCI (OR: 0.45, p < 0.001) and the availability of drug-eluting stents conferred a lower probability of choosing CABG (OR: 0.60, p = 0.003). Conclusions The majority of diabetic patients with multivessel disease were selected for PCI rather than CABG. Preference for CABG over PCI was largely based on angiographic features related to the extent, location, and nature of CAD, as well as geographic, demographic, and clinical factors. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305) (J Am Coll Cardiol Intv 2009;2:384-92) (C) 2009 by the American College of Cardiology Foundation

ANGIOTENSIN III MODULATES THE NOCICEPTIVE CONTROL MEDIATED BY THE PERIAQUEDUCTAL GRAY MATTER

Endogenous angiotensin (Ang) II and/or an Ang II-derived peptide, acting on Ang type I (AT(1)) and Ang type 2 (AT(2)) receptors, can carry out part of the nociceptive control modulated by periaqueductal gray matter (PAG). However, neither the identity of this putative Ang-peptide, nor its relationship to Ang II antinociceptive activity was clarified. Therefore, we have used tail-flick and incision allodynia models combined with an HPLC time course of Ang metabolism, to study the Ang III antinociceptive effect in the rat ventrolateral (vi) PAG using peptidase inhibitors and receptor antagonists. Ang III injection into the vIPAG increased tail-flick latency, which was fully blocked by Losartan and CGP 42,112A, but not by divalinal-Ang IV, indicating that. Ang III effect was mediated by AT(1) and AT(2) receptors, but not by the AT(4) receptor. Ang III injected into the vIPAG reduced incision allodynia. Incubation of Ang II with punches of vIPAG homogenate formed Ang III, Ang (1-7) and Ang IV. Amastatin (AM) inhibited the formation of Ang III from Ang II by homogenate, and blocked the antinociceptive activity of Ang II injection into vIPAG, suggesting that aminopeptidase A (APA) formed Ang III from Ang II. Ang III can also be formed from Ang I by a vIPAG alternative pathway. Therefore, the present work shows, for the first time, that: (i) Ang III, acting on AT(1) and AT(2) receptors, can elicit vIPAG-mediated antinociception, (ii) the conversion of Ang II to Ang III in the vIPAG is required to elicit antinociception, and (iii) the antinociceptive activity of endogenous Ang II in vIPAG can be ascribed preponderantly to Ang III. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.

Thiazolidinediones and type 2 diabetes: new drugs for an old disease

Thiazolidinediones are a new class of drugs for the treatment of type 2 diabetes, and act by improving insulin sensitivity in adipose tissue, liver and skeletal muscle. Rosiglitazone and pioglitazone are registered for use in monotherapy, and in combination with sulfonylureas and metformin. Pioglitazone is also licensed for use in combination with insulin. There is level II evidence that in patients with inadequate glycaemic control both drugs reduce the level of HbA(1c) and fasting plasma glucose (FPG) when used as monotherapy and in combination with sulfonylurea or metformin or insulin; and both drugs increase levels of HDL and LDL and lower free fatty acid levels, but only pioglitazone significantly lowers triglyceride levels. Both drugs lower fasting insulin and C-peptide levels. In monotherapy, they may be slightly less potent at reducing the level of HbA(1c) than sulfonylureas or metformin. The maximal effect of these agents may not be seen for 6-14 weeks after commencement. Both drugs are well tolerated but liver function must be checked at baseline every second month for the first year, and periodically thereafter. The drugs are currently contraindicated in patients with moderate to severe liver dysfunction and alanine aminotransferase levels more than 2.5 times normal, New York Heart Association III-IV cardiac status, pregnancy, lactation and in children. The main side effects include weight gain, oedema, and mild dilutional anaemia.

Synthesis, characterization and redox behaviour of benzoyldiazenido- and oxorhenium complexes bearing N,N- and S,S-type ligands

The reactions of [ReCl2{eta(2)-N2C(O)Ph}(PPh3)(2)](1) with 2-aminopyrimidine (H(2)Npyrm), 2,2'-bipyridine (bpy) and tetraethylthiuram disulfide (tds), in MeOH upon reflux, lead to the new eta(1)-(benzoyldiazenido)-rhenium(III) complexes [ReCl{eta(1)-N2C(O)Ph}(HNpyrm)(PPh3)(2)](2)and [ReCl2{eta(1)-N2C(O)Ph}(bpy)(PPh3)] (3), and the known oxo(diethyldithiocarbamato)dirhenium(v)complex [Re2O2(mu O){Et2NC(S)S}(4)](4), respectively. The Et2NC(S)S ligands in 4 result from S-S bond rupture of tds molecules. The obtained compounds have been characterized by IR, H-1, P-31{H-1} and C-13{H-1} NMR spectroscopies, FAB(+)-MS, elemental and single-crystal X-ray diffraction (for 2 and 4)analyses. Complex 2 represents the first structurally characterized Re compound derived from 2-aminopyrimidine. Besides, the redox behaviour of 2-4 in CH2Cl2 solution has been studied by cyclic voltammetry, and the Lever electrochemical ligand parameter (E-L)has been estimated, for the first time, for HNpyrm. The electrochemical results are discussed in terms of electronic properties of the Re centres and the ligands.

Synthesis and antioxidant activity of new xanthone-type compounds

3rd Portuguese Meeting on Medicinal Chemistry and 1st Portuguese-Spanish-Brazilian Meeting on Medicinal Chemistry, Aveiro, 28-30 Novembro 2012.

Hexanuclear and undecanuclear iron(III) carboxylates as catalyst precursors for cyclohexane oxidation

Two multinuclear complexes [Fe-6(mu(3)-O)(2)(mu(4)-O-2)L-10(OAc)(2)(H2O)(2)]center dot 2.625Et(2)O center dot 2.375H(2)O (1) and [(Fe11Cl)-Cl-III-(mu(4)-O)(3)(mu(3)-O)(5)L-16(dmf)(2.5)(H2O)(0.5)]center dot Et2O center dot 1.25dmf center dot 3.8H(2)O (2), where HL = 3,4,5-trimethoxybenzoic acid and dmf = dimethylformamide, have been prepared from trinuclear iron(III) carboxylates via their structural rearrangement in dimethylformamide or diethyl ether-dimethylformamide 9:1, respectively, and slow vapor diffusion of diethyl ether into the reaction mixture. Both compounds have been characterized by X-ray diffraction, optical, Mossbauer spectroscopy, and magnetic measurements. Complex 1 possesses a hexanuclear ferric peroxido-dioxido {Fe-6(O-2)(O)(2)}(12+) core unit, which adopts a recliner conformation, while complex 2 contains an unprecedented {Fe11O8Cl}(16+) core, in which 9 ferric ions are six-coordinate and the remaining two are five-coordinate. Another structural feature of note of the undecanuclear core is the presence of a deformed cubane entity {Fe-4(mu(3)-O)(mu(4)-O)(3)}(4+). Both complexes act as catalyst precursors for the oxidation of cyclohexane to cyclohexanol and cyclohexanone with aqueous H2O2, in the presence of pyrazinecarboxylic acid. Remarkable TONs and TOFs (the latter mainly for 1) with concomitant quite good yields have been achieved under mild conditions. Moreover, 1 exhibits remarkably high activity in an exceptionally short reaction time (45 min), being unprecedented for any metal catalyzed alkane oxidation by H2O2. The catalytic reactions proceed via Fenton type chemistry.

Molecular characterization of Dengue viruses type 1 and 2 isolated from a concurrent human infection

In 2001, an autochthonous case of dual viremia, resulting from naturally acquired dengue virus DEN-1 and DEN-2 infections was detected during the dengue outbreak that occurred in Barretos, a city with about 105,000 inhabitants in the North region of São Paulo State. Serotype identification was based on virus isolation to C6/36 mosquito cells culture and immunofluorescence assays using type-specific monoclonal antibodies. The double infection was also confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). Comparative analysis of the 240-nucleotide sequences of E/NS1 gene junction region between the genome of DEN-1 and DEN-2 isolates of the corresponding reference Nauru and PR 159S1 strains, respectively, showed some nucleotide differences, mainly silent mutations in the third codon position. Results of maximum likelihood phylogenetic analysis of E/NS1 gene sequences indicated that both genotypes of DEN-1 and DEN-2 viruses recovered from double infection in Barretos belonged to genotypes I and III, respectively.

Molecular typing of dengue virus type 2 in Brazil

Strain typing is a critical tool for molecular epidemiological analysis and can provide important information about the spread of dengue viruses. Here, we performed a molecular characterization of DEN-2 viruses isolated in Brazil during 1990-2000 from geographically and temporally distinct areas in order to investigate the genetic distribution of this serotype circulating in the country. Restriction site-specific polymerase chain reaction (RSS)-PCR presented the same pattern for all 52 Brazilian samples, showing the circulation of just one DEN-2 variant. Phylogenetic analysis using progressive pairwise alignments from 240-nucleotide sequences of the E/NS1 junction in 15 isolates showed that they belong to genotype III (Jamaica genotype).

Molecular analysis of the dengue virus type 1 and 2 in Brazil based on sequences of the genomic envelope-nonstructural protein 1 junction region

The genomic sequences of the Envelope-Non-Structural protein 1 junction region (E/NS1) of 84 DEN-1 and 22 DEN-2 isolates from Brazil were determined. Most of these strains were isolated in the period from 1995 to 2001 in endemic and regions of recent dengue transmission in São Paulo State. Sequence data for DEN-1 and DEN-2 utilized in phylogenetic and split decomposition analyses also include sequences deposited in GenBank from different regions of Brazil and of the world. Phylogenetic analyses were done using both maximum likelihood and Bayesian approaches. Results for both DEN-1 and DEN-2 data are ambiguous, and support for most tree bipartitions are generally poor, suggesting that E/NS1 region does not contain enough information for recovering phylogenetic relationships among DEN-1 and DEN-2 sequences used in this study. The network graph generated in the split decomposition analysis of DEN-1 does not show evidence of grouping sequences according to country, region and clades. While the network for DEN-2 also shows ambiguities among DEN-2 sequences, it suggests that Brazilian sequences may belong to distinct subtypes of genotype III.

The first crystal structure of class III superoxide reductase from Treponema pallidum

J Biol Inorg Chem (2006) 11: 548–558 DOI 10.1007/s00775-006-0104-y

Kinetics studies of the superoxide-mediated electron transfer reactions between rubredoxin-type proteins and superoxide reductases

J Biol Inorg Chem (2006) 11: 433–444 DOI 10.1007/s00775-006-0090-0

Basel III new capital requirements, impacts and bank behavior

For some years, researchers could not find a clear effect of capital adequacy on the risk profile of banks, as shareholders could increase the riskiness of the assets (qualitative effect), crowding-out the effect of reduced leverage (volume effect). Some shareholders might have the will to increase the riskiness of the assets, but they may lack the power to do so. Considering only ”powerful” shareholders, definitive conclusions were drawn but with constant ownership profile. In this paper I investigate whether there is a significant change in the type of shareholders in response to regulatory capital shocks and, if so, will the banking system be in the hands of more “desired” shareholders. I find that ownership profile responds to a regulatory shock, changing the risk appetite of the ruling power at the bank. I find more banks and the government in the ownership of undercapitalised banks and much less institutional shareholders and free float. I claim that these new shareholders may not the desired ones, given the objective of the regulatory change, as they are associated with a preference for more leverage. One possible explanation for this crowding-out effect is that regulators are trying to contain idiosyncratic risk (more linked to the riskiness of the assets) with a rule that contains systematic risk (capital adequacy). This has a distorting effect on ownership. Another insight can be drawn from the tests: supervisors should be aware of significant ownership movements that cause the crowding-out.

PEGylated DOTA-AHA-based Gd(III) chelates – A relaxometric study

Three PEGylated derivatives of 1,4,7,10-tetraazacyclododecane-1-((6-amino)hexanoic)-4,7,10-triacetic acid) (DOTA-AHA) with different molecular weights were prepared and characterized. Their Gd(III) chelates were studied in aqueous solution using variable-temperature 1H nuclear magnetic relaxation dispersion (NMRD) and 17ONMR spectroscopy in view of the determination of their relaxivity and the parameters that govern it. The relaxivity varied from 5.1 to 6.5 mM-1.s-1 (37 ºC and 60 MHz) with the increasing molecular weight of the PEG chain, being slightly higher than that of the parent chelate Gd(DOTA-AHA), due to a small contribution of a slow global rotation of the complexes. A variable temperature 1H NMR study of several Ln(III) chelates of DOTA-A(PEG750)HA allowed the determination of the isomeric M/m ratio (M = square antiprismatic isomer and m = twisted square antiprismatic isomer, the latter presenting a much faster water exchange) which for the Gd(III) chelate was estimated in circa 1:0.2, very close to that of [Gd(DOTA)]-. This explains why the PEGylated Gd(III) chelate has a water rate exchange similar to that of [Gd(DOTA)]-. The predominance of the M isomer is a consequence of the bulky PEG moiety which does not favor the stabilization of the m isomer in sterically crowded systems at the substituent site, contrary to what happens with less packed asymmetrical DOTA-type chelates with substitution in one of the four acetate C(α) atoms.

Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-Aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors

The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC50 10-28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 microM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.

A vegetação do município de Ilhéus, Estado da Bahia: III - caracterização da vegetação pelo valôr dos índices das espécies

The indices found are analysed as a whole and general conclusions are drawn from them which may be of use in understanding many of the problems offered by the local flora (Ilhéus). The first column of the tables presented indicates the biological form of the species, showing the nature of the flora and the constitution of the climax. A total of 200 species of phanerophyta were found; 69 macrophanerophyta (trees), 54 are mesophanerophyta (treelets) and 77 are nanophanerophyta (shrubs). The macrophanerophyta are consequently considered as dominants and the meso-and nanophanerophyta as codominants (the biological forms: chamaephyta, hemicriptophyta, criptophyta, geophyta, therophyta, epiphyta and hydrophyta are subdominants), the more so as the first cover 80% and the others more or less 50%. This points to a climax of trees and a local vegetation mainly composed of trees also. The smaller forms are left out as they are beyond the present scope of this sort of wort in Brazil. The third column of ecological formulae indicates the reaction of the constituent species to light (C = sciophilous, F = photophilous and I = indifferents), the biological types of vegetation (H = hygrophytes, X = xerophytes and M = mesophytes) and the fidelity of the species to the climax. Of the species studied: 25 are pioneers (P. Table I), 63 are accidentals (A. Table II), 35 are companion species (O. Table III), 19 show preferences (E. Table with vitality Vn), 44 are selective (S. Table V) and 13 exclusive species (L. Table VI). This leads to the conclusion that the vegetation of the region is in full reconstitution. As to the ecological characteristics of the 200 species studied, 89 are either pioneers (a class separated by the author) or accidentals; this means that the devastated zones are being reconstituted in the subsere both with members of the prisere and alien species. Of the remaining species, 54 are companion, or accompanying species, which appear in most subclimax, serclímax and quasiclimax associations, and 57 are real constituents of the local climax. As all the species except the pioneers, selectives and exclusives (xerophytes and mesophytes) may be considered as hygrophytes this type evidently predominantes in the region and may constitute a hygrophilous serclimax and quasiclímax. In regard to light 101 are sciophilous, 32 indiferents and 67 photophilous. This leads to the conclusion that the vegetation comprises mainly tolerant species, showing the hygrophilous and mesophilous character of the region with a vegetation composed mostly of trees. The presence a large number of sciophilous species is easy to understand as the hygrophilous and mesophilous habitats and the dominance of trees favour the germination and growth of tolerant species. The last two columns analyse the percentage of individuals present and the occurrent classes to which they belong: 92 species vary between 1 and 9%; 50 between to 10 and 19%; 36 between 20 and 29%; 14 between 30 and 39%; and 8 between 40 and 49%. Only 8 species belong to occurrence class V; 14 to classe IV; 36 to class III; 50 to class II; and 92 to class I. This leads to the conclusion that the local formation is very unsociable and very complex, though the median coverture is 80% and the number of species is very large. The analysis of the data also shows that the climax is being reconstituted in the subsere with elements drawn from the prisere and alien species introduced either by man (following desvastation) or by other consequent factors (such as brusque changes of microclimates due to total or partial destruction). This modifies the subclimax appreciably and apparently also the climax of the local regional subsere. As a final conclusion it is suggested that as in the subsere the pioneer formation is xerophilous, the prisere also beging as a xerosere; but as there are and probably always were hydrophilous formation evolving in the same climate, the local climax is composed of species with medium exactions, that is of relative mesophites.